The Effects Of Post-learning Alcohol Ingestion On Human Motor Memory Consolidation Part 3

4 | DISCUSSION

This work sought to investigate the neurochemical mechanisms of motor memory consolidation. 

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Informed by converging lines of human work on declarative memories (Bruce, Pihl, et al., 1999; Bruce, Shestowsky, et al., 1999; Bruce & Pihl, 1997; Carlyle et al., 2017; Doss et al., 2018; Lamberty et al., 1990; Mueller et al., 1983; Parker et al., 1980, 1981; Tyson & Schirmuly, 1994; Weafer et al., 2016), this work tested the hypothesis that postlearning alcohol ingestion-through its GABAergic agonist and NMDA antagonist properties (Abrahao et al., 2017; Grant & Lovinger, 2018)-would retrogradely enhance motor memory consolidation. The novelty of this work is that the results disconfirmed this hypothesis. 

Specifically, the results revealed that reach aftereffect levels during Dominant Hand Retention did not differ between the PBO, MED, and HIGH conditions, suggesting that ingesting medium (peak BrAC of
0.052%) or high (peak BrAC of
0.094%) alcohol doses following visuomotor adaptation did not enhance motor memory consolidation. 

Moreover, the results revealed that adaptation levels did not differ between conditions during the NonDominant Hand Session, that is when participants were under the influence of alcohol in the MED (BrAC of
0.027%) and HIGH conditions (BrAC of
0.073%). This suggests that alcohol did not disrupt motor adaptation capabilities, as assessed 60 min following its ingestion. 

Given alcohol's known pharmacological GABAergic agonist and NMDA antagonist properties, one possibility is that these neurochemical mechanisms do not contribute to motor memory consolidation. 

As decades of work demonstrated alcohol's retrograde declarative memory enhancements (Bruce, Pihl, et al., 1999; Bruce, Shestowsky, et al., 1999; Bruce & Pihl, 1997; Carlyle et al., 2017; Doss et al., 2018; Lamberty et al., 1990; Mueller et al., 1983; Parker et al., 1980, 1981; Tyson & Schirmuly, 1994; Weafer et al., 2016), the present results suggest that distinct neurochemical mechanisms underly declarative and motor memory consolidation.

4.1 | No effect of post-learning alcohol ingestion on motor memory consolidation

This work's main novel finding is that moderate and high alcohol doses neither significantly nor meaningfully altered motor memory consolidation as compared to placebo treatment. 

Namely, results from equivalence testing revealed that all between-condition effect sizes were negligible (absolute Cohen's dz <
0.2; see Table 6) and significantly greater and smaller than Cohen's dz values of 0.8 and 0.8, respectively, confirming that alcohol did not alter consolidation. Given alcohol's pharmacological properties (Abrahao et al., 2017; Grant & Lovinger, 2018), the present results further indicate that increasing GABAergic and decreasing NMDA receptor activity does not contribute to motor memory consolidation. 

Why do these results differ from declarative memory work (Bruce, Pihl, et al., 1999; Bruce, Shestowsky, et al., 1999; Bruce & Pihl, 1997; Carlyle et al., 2017; Doss et al., 2018; Lamberty et al., 1990; Mueller et al., 1983; Parker et al., 1980, 1981; Tyson & Schirmuly, 1994; Weafer et al., 2016) remains, however, unclear. A first possibility is that despite behavioral evidence showing interactions between motor and declarative memories (Feldman et al., 1995; Keisler & Shadmehr, 2010; Kim, 2020), their consolidation may be supported by distinct neurochemical mechanisms (Feld, Lange, et al., 2013; Feld, Wilhelm, et al., 2013; Kuriyama et al., 2011; Smith & Smith, 2003). 

For instance, Smith and Smith (2003) showed that alcohol ingestion immediately before sleeping prevented overnight improvements in motor but not declarative memories (see Feld, Wilhelm, et al., 2013, for similar results). Similarly, Feld, Lange, et al. (2013) found that DCycloserine (an NMDA receptor agonist) administration before sleeping enhanced declarative but not motor memory consolidation (although see Kuriyama et al., 2011). 

In further indirect support, earlier work showed inhomogeneous distributions of GABAA (Bowery et al., 1987; Young & Chu, 1990), GABAB (Bowery et al., 1987; Young & Chu, 1990), and NMDA (Petralia et al., 1994) receptors across mammalian cortical and subcortical structures, suggesting that alcohol does not similarly affect processes of memory consolidation located in distinct neural structures. The above and the present results suggest that pharmacologically altering GABAergic and NMDA activity does not similarly affect declarative and motor memory consolidation. One possibility is thus that distinct neurochemical processes underlie the consolidation of declarative and motor memories.

A second possibility is that reaching asymptotic performance levels during the present Hold phase initiated memory consolidation (Hamel et al., 2017; Orban de Xivry et al., 2011; Yin & Kitazawa, 2001), which prevented alcohol from altering it. In support, Hadj Tahar et al. (2005) had participants ingest Amantadine (an NMDA receptor antagonist) after asymptotic performance levels were reached during a joystick motor adaptation task. 

Their results revealed no significant performance difference 24 h later between Amantadine and placebo treatment, suggesting that reaching performance asymptote prevented Amantadine from altering memory consolidation. 

Moreover, Shibata et al. (2017) recorded MRS data and showed that overlearning a visual orientation detection task shifted excitatory-dominant to inhibitory-dominant glutamate and GABA concentrations in visual areas, suggesting that reaching performance asymptote initiates consolidation by increasing endogenous inhibition of neural activity. One possibility is thus that pharmacological agents inhibiting neural activity effectively enhance consolidation when inhibition has not already been endogenously increased by reaching performance asymptote.

A third possibility is that alcohol doses previously used to enhance declarative (e.g., Parker et al., 1981) memories-also used in the present work-are insufficient to enhance motor memory consolidation. 

In support, Hernandez et al. (2006, 2007) showed that aspects of cognitive but not motor performance were impaired by reaching BrAC values of
0.07%, suggesting that greater alcohol doses are required to perturb the motor system. 

This evidence also echoes alcohol's effects on human behaviors, which are primarily cognitive at doses yielding BrAC values up to
0.12% (e.g., euphoria, talkativeness, and impaired attention) and broaden to motor impairments at doses yielding BrAC values of
0.15% and above (e.g., impaired balance, coordination, and gait) (Jones, 2019; Pohorecky & Brick, 1988). One possibility is thus that alcohol doses greater than those used to enhance declarative memories are required to influence motor memory consolidation.

Perplexingly, while alcohol appears to ubiquitously enhance declarative memory consolidation in humans (Bruce, Pihl, et al., 1999; Bruce, Shestowsky, et al., 1999; Bruce & Pihl, 1997; Carlyle et al., 2017; Doss et al., 2018; Lamberty et al., 1990; Mueller et al., 1983; Parker et al., 1980, 1981; Tyson & Schirmuly, 1994; Weafer et al., 2016), its effects on consolidation are not as consensual in animal work (Alkana & Parker, 1979; Aversano et al., 2002; Castellano & Pavone, 1983; Castellano & Pavone, 1988; Colbern et al., 1986; de Carvalho et al., 1978). 

Namely, using passive avoidance tasks and alcohol doses that are twofold to fivefold those used in human work, early rodent work showed that post-learning alcohol injection enhances (Alkana & Parker, 1979; Colbern et al., 1986), disrupts (Aversano et al., 2002; Castellano & Pavone, 1983, 1988) or does not alter memory consolidation (de Carvalho et al., 1978). 

As this evidence suggests that alcohol heterogeneously affects passive avoidance memory consolidation in animals, its relationship to the previous (Bruce, Pihl, et al., 1999; Bruce, Shestowsky, et al., 1999; Bruce & Pihl, 1997; Carlyle et al., 2017; Doss et al., 2018; Hewitt et al., 1996; Lamberty et al., 1990; Mueller et al., 1983; Parker et al., 1980, 1981; Scholey & Fowles, 2002; Tyson & Schirmuly, 1994; Weafer et al., 2016) and present work remains, however, unclear. 

Finally, although classified as a central nervous depressant, it should be noted that alcohol has stimulating properties (Hendler et al., 2013); has dopaminergic, noradrenergic, and serotoninergic agonist properties (Abrahao et al., 2017), and widespread molecular targets (e.g., opioid and endocannabinoid receptors, neuropeptides such as corticotropin-releasing factor and intracellular signaling molecules such as protein kinase C, respectively) (Abrahao et al., 2017). How these additional properties of alcohol relate to human motor memory consolidation remains a query for future work.

4.2 | Alcohol did not alter learning during adaptation with the non-dominant hand

Another novel finding is that alcohol did not impair adaptation during Non-Dominant Hand Sessions, evidenced by the lack of significant difference across the PBO, MED, and HIGH conditions. As above, results from equivalence testing revealed that all between-condition effect sizes were small (absolute Cohen's dz <
0.3; see Table 4) and significantly greater and smaller than Cohen's dz values of 0.8 and 0.8, respectively, confirming that alcohol did not acutely alter adaptation capabilities. 

However, the results also revealed that movements were faster and accuracy was lesser in the HIGH as compared to the PBO condition, confirming that the effects of alcohol on motor performance were not completely absent. While resonating with its null result on consolidation, the null effect of alcohol on adaptation opposes work showing that alcohol acutely impairs cerebellar-dependent motor coordination and learning in animals (He et al., 2013; Sullivan et al., 1995; Valenzuela et al., 2010; Zorumski et al., 2014). 

However, as GABA and NMDA receptors were reported to increase or decrease their activity during motor learning in humans (Donchin et al., 2002; Floyer-Lea et al., 2006; Hadj Tahar et al., 2004; Kolasinski et al., 2019; van Vugt et al., 2020), the implications of this evidence remain unclear. For instance, Donchin et al. (2002) showed that administering lorazepam (a GABAA agonist) or dextromethorphan (an NMDA antagonist) before learning impaired forcefield adaptation as compared to placebo, suggesting that pharmacological agents with properties similar to those of alcohol impair sensorimotor adaptation. 

However, human MRS studies have shown that M1 GABA concentrations either decrease (Floyer-Lea et al., 2006; Kolasinski et al., 2019) or increase (van Vugt et al., 2020) during learning of motor tasks, contributing to GABAergic activity to motor learning unclear. Furthermore, Hadj Tahar et al. (2004) showed that Amantadine ingestion before joystick motor adaptation did not significantly impair learning capabilities, questioning if intact NMDA receptor activity is necessary for motor adaptation. Overall, the above and present results suggest that the contributions of GABAergic and NMDA activity to human sensorimotor adaptation remain unclear, warranting further investigations.

4.3 | Limitations

One limitation is that the HIGH, MED, and PBO beverages were all mixed with orange juice, which contained glucose. Although the effect of glucose on motor memory consolidation remains unknown, it could have influenced motor memory consolidation similar to alcohol, thus concealing its effect (Scholey & Fowles, 2002). 

In support, Scholey and Fowles (2002) found that post-learning ingestion of alcohol (0.38 g/kg) and glucose (25 g) beverages similarly enhanced the early consolidation of kinesthetic memories as compared to a saccharin PBO. 

Future work should replicate the present results using sugar-free beverage solutions. Another limitation is that sleep quality was not objectively measured, suggesting that alcohol could have failed to enhance motor memory consolidation by interfering with sleep patterns (see Smith & Smith, 2003, for support). The relationship between post-learning alcohol ingestion, sleep patterns, and motor memory consolidation remains a query for future work.

5 | CONCLUSION

This study's objective was to investigate the neurochemical mechanisms of human motor memory consolidation.

Informed by converging work showing that alcohol retrogradely enhances declarative memory consolidation, this work tested the hypothesis that post-learning alcohol ingestion would enhance motor memory consolidation as compared to placebo treatment. 

However, the results disconfirmed this hypothesis by showing that neither medium nor high doses of alcohol enhanced motor memory consolidation as compared to placebo. As this directly opposes studies on human declarative memories, the present results suggest that GABA and NMDA receptor activity distinctly contribute to declarative and motor memory consolidation. 

Elucidating the neurochemical mechanisms underlying the consolidation of different memory systems may yield insights into the effects of over-the-counter drugs on everyday learning and memory, but also inform pharmacological interventions seeking to alter human memory consolidation (e.g., reconsolidation of pathogenic memories; see Diergaarde et al., 2008; Elsey et al., 2018; Walsh et al., 2018).

ACKNOWLEDGEMENT

This work was funded by the Natural Sciences and Engineering Research Council of Canada (Grant number: 418589).

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.

AUTHOR CONTRIBUTIONS

R.H. designed the experiment, collected the data, conducted the analyses, prepared the figures, and wrote the manuscript. O.D. helped to design the experiment, collected the data, helped to conduct the analyses, helped to prepare the figures, and helped to write the manuscript. J.F.L. and P.M.B. helped to design the experiment and revised the manuscript.

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