Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks

In the paper

“Systemic administration of an α1 agonist that crosses the blood brain barrier also impairs working memory performance, while administration of an α1 antagonist, e.g., prazosin, can protect working memory performance during stress (37,50,51).”

What the sources say

• Partly supported

  The Discussion reports that α1 stimulation in the prefrontal cortex impairs spatial working memory and that intra-PFC urapidil reversed a pharmacological stressor’s effect on response accuracy in rats (page not available in our copy). It does not establish that a blood–brain-barrier-crossing α1 agonist was administered systemically, or that prazosin protected working memory during stress; its prazosin example concerns performance under nonstress conditions. (LLM, conf=0.86)

  cites [37] Birnbaum, 1999, A role for norepinephrine in stress-induced cognitive deficits: Alpha-1-adrenoceptor mediation in the prefrontal cortex, Biol Psychiatry sourceExperimental — accuracy not yet measured
• Partly supported

  The Drug Administration and Results sections report systemic cirazoline treatment in aged monkeys, impaired spatial working memory, and reversal of that impairment by prazosin (page numbers unavailable). The Discussion proposes that α1 mechanisms may contribute to cognitive impairment during stress, but the paper does not show that prazosin protects working memory during stress. It describes cirazoline's brain penetrance as purported rather than directly demonstrating it. (LLM, conf=0.88)

  cites [50] Arnsten, 1997, The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged monkeys, Pharmacol Biochem Behav sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [51] Arnsten, 1999, Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function, Biol Psychiatry source

In the paper

“Like methylphenidate, atomoxetine also blocks the NE transporter (Figure 2E), and as the NE transporter clears both NE and DA in the PFC, this increases extracellular levels of both catecholamines (90).”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports that atomoxetine inhibits the NE transporter, that this transporter takes up dopamine in the PFC, and that atomoxetine increases extracellular NE and dopamine there. It presents transporter-mediated dopamine clearance as a proposed explanation, however, and says other interactions may also contribute; the citing sentence states that causal explanation more definitively than the paper does. (LLM, conf=0.82)

  cites [90] Bymaster, 2002, Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder, Neuropsychopharmacology sourceExperimental — accuracy not yet measured

In the paper

“A common misconception is that methylphenidate is a selective DA transporter blocker, when in actuality it blocks both NE and DA transporters. Indeed, methylphenidate has more potent effects on NE than DA in the rat PFC (83) (84).”

What the sources say

• ?Not checked — no full text of the sourcecites [83] Berridge, 2006, Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function, Biol Psychiatry source
• Partly supported

  The section “Neurochemical Actions of Low-Dose Psychostimulants” (page not supplied) states that methylphenidate blocks both NE and DA reuptake and increases both in the rat PFC. It does not say that its effects on NE are more potent than its effects on DA in the rat PFC. (LLM, conf=0.86)

  cites [84] Berridge, 2011, Psychostimulants as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder, Biol Psychiatry sourceExperimental — accuracy not yet measured

In the paper

“Data from studies of monkey dorsolateral PFC demonstrate an inverted-U dose-response: moderate levels of NE released during alert, nonstressed waking improve working memory performance by engaging postsynaptic, α2A receptors (35,36), whereas high levels of NE released during stress impair PFC function via stimulation of lower affinity α1 (37) and β1 receptors (38).”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Arnsten, 1985, Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates, Science source
• ?Not checked — no full text of the sourcecites [36] Li, 1994, Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys, Behav Neural Biol source
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [37] Birnbaum, 1999, A role for norepinephrine in stress-induced cognitive deficits: Alpha-1-adrenoceptor mediation in the prefrontal cortex, Biol Psychiatry sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [38] Ramos, 2005, The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys, Biol Psychiatry source

In the paper

“Norepinephrine has the highest affinity for α2 adrenergic receptors and lower affinity for α1 and β receptors (34).”

What the sources say

• Supported

  The discussion and Fig. 4 caption (pp. 141–142) state that norepinephrine has higher affinity for α2A receptors than for α1 or β receptors. The claim paraphrases this comparison, using the broader α2 label for the α2A subtype specified in the paper. (LLM, conf=0.93)

  cites [34] Arnsten, 2000, Through the looking glass: Differential noradenergic modulation of prefrontal cortical function, Neural Plast source

In the paper

“Cognitive studies in animals have shown that either blockade of D1/5 receptors or excessive stimulation of D1/5 receptors in the PFC impairs spatial working memory (106–108).”

What the sources say

• Not checked yetcites [106] Arnsten, 1990, Stress impairs prefrontal cortex cognitive function in monkeys: Role of dopamine, Soc Neurosci Abstr
• ?Not checked — no full text of the sourcecites [107] Sawaguchi, 1991, D1 dopamine receptors in prefrontal cortex: Involvement in working memory, Science source
• Partly supported

  The paper reports that excessive D1 receptor stimulation in rat PFC impaired delayed-alternation performance, a spatial working-memory task. Its introduction also describes evidence that insufficient D1 stimulation impairs PFC cognition, but this study’s antagonist dose alone did not impair performance (Experiment 2, page unavailable). The passages identify D1 receptors, not D1/5 receptors, so the D5 part of the claim is not established by this source. (LLM, conf=0.86)

  cites [108] Zahrt, 1997, Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance, J Neurosci sourceExperimental — accuracy not yet measured

In the paper

“The D2 receptors are less prevalent in monkey dorsolateral PFC and are concentrated on layer V neurons, the layer that projects to striatum and the superior colliculus (98,122,123).”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Lidow, 1998, Layer V neurons bear the majority of mRNAs encoding the five distinct dopamine receptor subtypes in the primate prefrontal cortex, Synapse source
• Partly supported

  The Discussion reports that D2 binding sites are considerably less concentrated in primate cortex than in the neostriatum, and the Results report binding in monkey prefrontal cortex. The paper does not establish that receptors are concentrated on layer V neurons or identify layer V projections to the striatum and superior colliculus; it measures binding by cortical region, not neuronal layer. (LLM, conf=0.86)

  cites [122] Lidow, 1989, Dopamine D2 receptors in the cerebral cortex: Distribution and pharmacological characterization with [3H]raclopride, Proc Natl Acad Sci U S A sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [123] Lidow, 1991, Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390, Neuroscience source

In the paper

“Dopamine neurons have not been followed as methodically with regard to states of arousal but have been shown to fire related to prediction of reward (28).”

What the sources say

• ?Not checked — no full text of the sourcecites [28] Schultz, 1998, The phasic reward signal of primate dopamine neurons, Adv Pharmacol source

In the paper

“Stimulation of α2A receptors increases delay-related firing of PFC neurons via inhibition of cyclic adenosine mono-phosphate (cAMP) (57), while stimulation of α1 receptors decreases delay-related firing via activation of phosphatidylinositol protein kinase C signaling (58).”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
• ?Not checked — no full text of the sourcecites [58] Birnbaum, 2004, Protein kinase C overactivity impairs prefrontal cortical regulation of working memory, Science source

In the paper

“Stimulation of α2A receptors strengthens firing for the neuron’s preferred direction by inhibiting cAMP production, which, in turn, reduces cAMP opening of potassium channels, increasing the efficacy of nearby synaptic inputs (Figure 2E).”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source

In the paper

“The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function.”

What the sources say

• ?Not checked — no full text of the sourcecites [4] Brozoski, 1979, Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey, Science source
• ?Not checked — no full text of the sourcecites [5] Arnsten, 1985, Stress produces opioid-like effects on investigatory behavior, Pharmacol Biochem Behav source
• ?Not checked — no full text of the sourcecites [6] Roberts, 1994, 6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: Possible interactions with subcortical dopamine, J Neurosci source
• ?Not checked — no full text of the sourcecites [7] Robbins, 2007, Differential regulation of fronto-executive function by the monoamines and acetylcholine, Cereb Cortex source

In the paper

“Either depletion of NE (35) or blockade of α2A receptors in PFC (36) impairs working memory performance in monkeys, suggesting that endogenous NE plays a large role in strengthening working memory performance.”

What the sources say

• ?Not checked — no full text of the sourcecites [35] Arnsten, 1985, Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged nonhuman primates, Science source
• ?Not checked — no full text of the sourcecites [36] Li, 1994, Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys, Behav Neural Biol source

In the paper

“Norepinephrine neurons in the locus coeruleus are silent during rapid eye movement sleep and have low tonic firing during slow wave sleep, moderate tonic firing and pronounced phasic firing to relevant stimuli during nonstressed waking, and high tonic firing with dysregulated phasic firing during stress (27).”

What the sources say

• ?Not checked — no full text of the sourcecites [27] Aston-Jones, 1999, Role of locus coeruleus in attention and behavioral flexibility, Biol Psychiatry source

In the paper

“These studies have revealed that NE and DA have complementary effects on the strength of PFC network connections, with NE strengthening connectivity via α2A receptor stimulation and DA sculpting network inputs via D1 receptors.”

In the paper

“Iontophoresis of an α2A agonist such as guanfacine onto PFC neurons enhances neuronal firing during the delay period for the neurons’ preferred direction (Figure 3A), while blockade of α2A receptors markedly reduces PFC neuronal firing during the delay period (indeed, high doses can silence a neuron) (57,61).”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
• ?Not checked — no full text of the sourcecites [61] Li, 1999, Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys, Neuropsychopharmacology source

In the paper

“All medications currently approved for the treatment of ADHD influence NE transmission (Figure 2E), and all can improve at least some aspects of PFC function (82).”

What the sources say

• ?Not checked — no full text of the sourcecites [82] Chamberlain, 2011, Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery, Biol Psychiatry source

In the paper

“Animal studies have also shown that the enhancing effects of methylphenidate and atomoxetine on working memory performance involve D1/5 receptor stimulation, as well as the NE α2 receptor actions described above.”

In the paper

“Studies of catecholamine actions on dorsolateral PFC microcircuitry have revealed intricate and powerful mechanisms to regulate the strength of persistent neuronal firing and the degree of neuronal tuning.”

In the paper

“Iontophoresis of D2 drugs onto PFC neurons has no effect on delay cell firing during the delay period in a working memory task but has marked effects on response cell firing in relationship to the eye movement response (124).”

What the sources say

• ?Not checked — no full text of the sourcecites [124] Wang, 2004, Selective D2 receptor actions on the functional circuitry of working memory, Science source

In the paper

“On the other hand, stimulants likely enhance motivation and other striatal functions not engaged by NE medications (135).”

What the sources say

• ?Not checked — no full text of the sourcecites [135] Cousins, 1996, Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task, Behav Brain Res source

In the paper

“Thus, DA and NE have complementary roles: NE α2A receptor stimulation enhances network firing for shared, preferred inputs (i.e., increasing signals [57]), whereas D1 receptor stimulation sculpts neuronal firing by decreasing firing to nonpreferred inputs (i.e., decreasing noise [109]).”

What the sources say

• ?Not checked — no full text of the sourcecites [57] Wang, 2007, Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex, Cell source
• ?Not checked — no full text of the sourcecites [109] Vijayraghavan, 2007, Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory, Nat Neurosci source