Brain tyrosine depletion attenuates haloperidol-induced striatal dopamine release in vivo and augments haloperidol-induced catalepsy in the rat

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.

Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Acute Serotonin and Dopamine Depletion Improves Attentional Control: Findings from the Stroop Task

Scholes

Harrison

O’Neill

et al. 2006

“…These depletion levels are equivalent to those observed using ATPD in previous studies (Harmer et al, 2001;Leyton et al, 2000). Furthermore, APTD studies with depletion levels of this magnitude have noted significant reductions in catecholamine metabolites (Palmour et al, 1998) and catecholamine synthesis (Jaskiw and Bongiovanni, 2004;McTavish et al, 1999a, b), and significant increases in plasma prolactin levels (an indirect measure of dopamine function) (Harmer et al, 2001). However, depletion of dopamine with ATPD in the present study resulted in no significant change in either PPI or P50 suppression.…”

Section: Dopamine Depletionsupporting

confidence: 80%

“…Using this method, serotonin depletion was found to decrease PPI in healthy humans (Phillips et al, 2000a). On the other hand, acute tyrosine/phenylalanine depletion (ATPD) has been shown to selectively decrease dopamine synthesis and release (Jaskiw and Bongiovanni, 2004;Leyton et al, 2000;McTavish et al, 1999aMcTavish et al, , b, 2001aMehta et al, 2005;Montgomery et al, 2003), and impair dopamine-dependent cognitive processes such as working memory (Harmer et al, 2001;Harrison et al, 2004). The effects of dopamine depletion via ATPD on PPI and P50 suppression are yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

Mann

Croft

Scholes

et al. 2007

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/ phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal 'gating' function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

“…Nevertheless, it is theoretically possible that these increases have less than expected impact on catecholamine synthesis because of enhanced tyrosine metabolism via other routes or poor tyrosine entry into the catecholamine neurons. Lower doses of tyrosine (100 mg/ kg) were sufficient to reverse the effects of tyrosine depletions in other studies (Jaskiw and Bongiovanni, 2004) but this involved a model in which the activity of tyrosine hydroxylase was activated, and thereby more sensitive to substrate availability.…”

Section: Discussionmentioning

confidence: 97%

Effect of Acute Tyrosine Depletion in Using a Branched Chain Amino-Acid Mixture on Dopamine Neurotransmission in the Rat Brain

Masurier

Oldenzeil

Lehman

et al. 2005

Central dopamine function is reduced by decreasing the availability of the catecholamine precursor, tyrosine, using a tyrosine-free amino acid mixture containing multiple large neutral as well as branched chain amino-acids, which compete with tyrosine for uptake into the brain. Current mixtures are cumbersome to make and administer, and unpalatable to patients and volunteers. Here, we investigate whether individual or limited amino-acid combinations could reduce brain tyrosine levels and hence dopamine function. Measurements of regional brain tyrosine levels, catecholamine and indoleamine synthesis (L-DOPA and 5-HTP accumulation, respectively) were used to identify an effective paradigm to test in neurochemical, behavioral and fos immunocytochemical models. Administration of leucine or isoleucine, or a mixture of leucine, isoleucine, and valine reduced tyrosine and 5-HTP, but not L-DOPA accumulation. A mixture of leucine, valine, and isoleucine supplemented with tryptophan reduced brain tyrosine and L-DOPA, but not 5-HTP. In microdialysis experiments this amino-acid mixture reduced basal and amphetamine-evoked striatal dopamine release, as well as amphetamine-induced hyperactivity. This mixture also reduced amphetamine-induced fos expression in striatal areas. In conclusion, the present study identified a small combination of amino acids that reduces brain tyrosine and dopamine function in a manner similar to mixtures of multiple amino acids. This minimal mixture may have use as a dopamine reducing paradigm in patient and volunteer studies.