Review: Li, Huang, Chen, Hyland, and Wickens, Phasic Dopamine Signals are Reduced in the SHR Rat and by Methylphenidate

Introduction: A summary is provided about ADHD and its treatment with stimulant drugs. The study addresses complicated issues about effects of the neurotransmitter dopamine that have been addressed by eminent experts for decades related to:
(a) the dopamine deficit hypothesis of ADHD and for the clinical effects of stimulant medication for the treatment of ADHD, which was proposed 50 years ago as a general catecholamine deficit (Wender, 1970) -- and is still the most accepted neurobiological hypotheses of ADHD;
(b) the SHR rat as an animal model for ADHD, which was proposed 30 years ago (Sagvolden et al, 1992)0, which is based on the general concept that a dopamine deficit would be associated with a steep delay of reinforcement gradient -- and still seems to be one of the best available animal models of ADHD;
(c) a specific mechanism of action of stimulant drugs when used to treat ADHD, which was proposed more than 20 years ago by Seeman and Madras (1998) and suggested that these drugs that are considered dopamine agonists (and might be expected to increase activity) instead clearly have a clinical effect or benefit associated with reduction of "hyperactivity", due to homeostatic processes related to tonic and phasic dopamine – that is still viable;
(d) the dopamine transfer deficit (DTD) theory of ADHD, which was proposed more than 15 years ago (Tripp and Wickens, 2008), based on observations regarding the effects of delayed and partial reinforcement in children with ADHD and the effects of dopamine on reinforcement and learning depend on the reduced effect of a cue that predicts reinforcement for the critical dopamine signal provided by a burst due to the phasic release of dopamine in the brain.

Methods: Sophisticated techniques are described. The study used precise timing and magnitude of electrical stimulation by implanted electrodes in dopamine regions (SNC and VTA) of the brain in SHR (n = 7) and control Sprague-Dawley (SD, n = 6) rats. The electrical stimulation was initially paired with visual and auditory stimulation for 50 trials on the first day of 7 tests days, and on days 2 to 7 for 25 trials before and after a range of dose of methylphenidate (0, 0.2, 0.5, 2.0, 5.0, and 20.0 mg/kg). Only three of these doses were considered in the results and discussion provided here (0, 0.5. and 2.0 mg/kg).

Results: The primary findings are clear. Figure 2 summarizes differences between the groups of SHR and SD rats for the "learned" dopamine responses to the Cue and Stimulus, and Figure 4 summarizes an interaction of dopamine response to an i.p dose in the two strains of rats:
(a) the relevant effect in Figure 2b is shown as an increasing level of dopamine over trials in the initial response to the Cue);
(b) the relevant effect in Figure 2b is shown as a decreasing level of dopamine over trials in the response to the paired Stimulus).
(c) the relevant effect in Figure 4e is shown for the peak change in dopamine after the Cue for the 3 doses of 0, 0.5, and 2.0 mg/kg (which after the low dose increased for the SHR but not for the SD rats);
(d) the relevant effect shown in Figure 4f is for the peak change in dopamine after the Stimulus for the 3 doses (which did not increase after the low dose for either SHR or SD rats).

Summary: A brief summary emphasized that the dopamine response to the Cue and the Stimulus was lower in the ADHD-like animals (the SHR rats) than the non-ADHD animals (the SD rats), as shown in Figure 2, and emphasized that the response to methylphenidate (which blocks the dopamine transporter) "selectively increased the cue response and not the electrically stimulated response in the SHR and did not increase the cue response in the SN" (page 14). Three main findings were described: (a) An increased dopamine response to the Cue over trials but decreased response to the Stimulus; (b) lower dopamine response in the SHR than SN animals, and (c) selective response to the low dose of methylphenidate in the SHR animals.

Discussion: A long discussion was provided to interpret these findings under separate heading related to associated with complexities in the literature: (a) the "Smaller amplitude of phasic dopamine signal in SHR (i.e., the "dopamine deficit" in ADHD-like animals), (b) “Sprague Dawley rats as the companion strain" (i.e., as non-ADHD-like animals), (c) "Clearance of dopamine is slower in SHR than SD rats (i.e., a low level of the dopamine transporter as possible source of the "dopamine deficit"), (d) "Transfer of the dopamine signal is similar in SHR and SD rats" (i.e., an intact learning process but with a decrease in both strains over time that may be associated with an increase GABA-mediated inhibition), (e) "Methylphenidate increase phasic dopamine response" (i.e., lack of support for the Seeman/Madras hypothesis that methylphenidate may result have an net effect of decreasing dopamine level due to the effects of auto-receptors inhibiting the release of dopamine in addition to blocking the re-uptake of dopamine), (f) "Low dose methylphenidate selectively increases dopamine release evoked by sensory cues in the SHR" (i.e., the drug effect of blockade of reuptake of dopamine without a homeostatic decrease in release would result in a net increase in phasic dopamine, which would increase the salience of the cue and the effect of the cue as a conditioned reinforcer of behavior).

REVIEW:

The technical quality of the work is high: this study is based on (a) two well-established and important neurobiological accounts of attention-deficit/hyperactivity disorder (ADHD), the spontaneously hypertensive rate (SHR) animal model and the dopamine transfer deficit (DTD) neurotransmitter theory; (b) sophisticated measures of the neurotransmitter dopamine and specifically on the phasic increases in dopamine using an in vivo method, fast-scan cyclic voltammeter (FSCV); (c) the use of sophisticated electrical stimulation of neural regions associated with dopamine, the substantial nigra and ventral regimental area of the brain.

The relevance of the study to the aims and goals of EJN are clear: (a) ADHD is the most commonly diagnosed and treated psychiatric disorder of childhood, so the topic is very clinical relevant; (b) dramatic secular trends have resulted in about 10-fold increases over the past 50 years (from 1970 to 2020) in diagnosis and treatment of ADHD, so this is a very controversial topic; (c) well-established concepts and methods from neuroscience were applied to address a widespread clinical practices and enduring controversies about their current status.

The primary findings are clear and important: (a) the reported effects of reward-predicting cues in ADHD-like SHR animals (e.g., a reduced phasic dopamine response) and the selective effects of low doses of methylphenidate (relative increases in the phasic dopamine response to cues) are consistent with expectations from previous studies; b) the extensive discussion of six areas of complexities related to these effects provides some additional information about the how stimulant medications may produce clinical benefits in the treatment of ADHD.; (c) the critical finding (i.e., differential effect of methylphenidate “in response to sensory cues or electrical stimulation” that cannot be explained by the local blockade of the dopamine transporter in the striatum”) is important, since (as suggested) these differential effects are likely due to “other sites outside the striatum”.

There are some additional issues that could be discussed (even though the discussion section is already long – about 8 of the 18 pages of the manuscript):

(a) The authors report they “found no support for the Seeman hypothesis”, but in another recent study the same group (Fuller et al., 2019 with Wickens and Hyland as co-authors) concluded “in order to understand the net effect of systemic methylphenidate on dopamine response in the striatum to reward stimuli it is necessary to take into account feedback effects [and] core to this scenario is the Seeman and Madras hypothesis”. It seems reasonable that this previous study and its conclusions should be mentioned and discussed in this manuscript by Li et al. (also with Wickens and Hyland as co-authors).
(b) The decreasing effect of electrical stimulation and the reduction of phasic dopamine over trials was described, and GABA-mediated inhibition was suggested to account for this. This possibility could be described in more detail, and perhaps relate this to other effects that are discussed (i.e., the general reduced phasic dopamine response in SHR animals and the reduced effect of reward-predicting cues).
(c) The effects of “treatment methylphenidate were analyzed using a before and after design”, and the peak values “before and after were converted to a change scores”. Are there concerns about regression to the mean based on this design and method? Have the classic issues described in many articles (e.g., see Oldham, 1962; Blomqvist, 1977; Bland and Altman, 1994; Yudkin and Stratton, 1996; Blance, Tu, and Gilthorpe, 2005; etc.) been addressed?
(d) Perhaps the authors could contrast the current and previous findings and conclusions, and perhaps relate the difference to some methodological differences in the two studies, which may have contributed to the different conclusions in the previous study and the present study. I realize that Fuller et al (2019) valuated a different strain of animals (Wistar rats) and used a single dose of methylphenidate (i.p. 5 mg/kg).
(e) Maybe I misunderstood that study, and a comparison is not appropriate, but could the authors explain why the 5 mg/kg dose in the present study increase phasic dopamine (see Supplementary Figure S1) but previously in the study reported by Fuller et al (2019) the same dose (5 mg/kg) of “methylphenidate alone had no effect on the amplitude of phasic response to cues or reward”?