During adolescence, chemicals and cells in the brain undergo significant reorganization. These changes are thought to be why teenagers are often more vulnerable to developing drug addictions and psychiatric disorders. However, it is not fully understood how the brain transforms during this transitional period.

Most of this reorganization takes place in the dopamine system which is responsible for triggering pleasurable sensations, including the feeling of reward after taking drugs. In 2020, a group of researchers found that adolescent male rats released less of the chemical dopamine in a part of the brain involved in the reward pathway than adult rats. But it was unclear what was causing this age-related effect.

To investigate, Iacino et al. – including some of the researchers involved in the 2020 study –blocked a family of receptors called nAChRs (short for nicotinic acetylcholine receptors) in the brain cells of male rats. These receptors bind to a neurotransmitter called acetylcholine which stimulates cells to release dopamine. Iacino et al. found that inhibiting a specific type of nAChR led to a decrease in dopamine in adult rats, but an increase in early adolescent rats. However, this effect was not observed when other types of nAChRs were inhibited.

Iacino et al. found that the adolescent male rats also had higher levels of another neurotransmitter called GABA which blocks the release of dopamine. This led them to hypothesize that the reduced levels of dopamine in early adolescence may be due to increased levels of GABA, which is secreted by specialized cells which also have nAChRs on their surface.

To investigate, Iacino et al. blocked two receptors for GABA that are found on dopamine-releasing neurons before exposing the rats to the nAChR inhibitor. This caused the adolescent rats to release less dopamine following nAChR inhibition, similar to the levels observed in adult rats. These findings suggest that the nAChR inhibitor leads to a rise in dopamine by stopping cells from releasing GABA – but only in adolescent rats.

The work of Iacino et al. demonstrates how the dopamine system differs in adolescence, which may provide new insights in to why teenagers are often more susceptible to addiction. For instance, nicotine, the addictive substance in cigarettes, can also bind to nAChRs and make them less sensitive to acetylcholine. This may reduce the release of GABA, resulting in more dopamine being released which is then sensed as a reward by the teenage brain. However, more research is needed to fully understand how this brain circuit is modulated by nicotine intake.

Adolescence is the transitional period between childhood and adulthood characterized by changes in behaviors, such as increases in risk-taking, sensation seeking, and peer-focused sociality (Spear, 2000; Spear, 2011; Spear, 2013; Nelson et al., 2005). These behavioral changes are thought to be evolutionarily advantageous, as they allow for the exploration necessary for a transition to independence (Spear, 2000). However, adolescence is also a time of increased vulnerability to the development of a range of psychiatric disorders, including substance use disorders (SUD), schizophrenia, and affective disorders, that can persist into adulthood (Casey et al., 2008; Fareri et al., 2008; Steinberg, 2008). Adolescent onset is also associated with increased severity of a range of psychiatric disorders (Chambers et al., 2003; Kyriakopoulos and Frangou, 2007; Andersen and Teicher, 2008). This may be, in part, because the brain is still developing during this vulnerable period and disturbances, such as drug-taking or stress, may disrupt the natural developmental trajectory. Thus, understanding how the adolescent brain develops in a normative state may help us pinpoint how and why this system is perturbed in disease.

Reorganization of the dopamine system is hypothesized to underlie many of the changes in adolescent behavior, particularly in reward-related learning and decision-making, and the increased vulnerability to developing psychiatric disorders (Spear, 2000; Spear, 2013; Nelson et al., 2005; Wahlstrom et al., 2010a; Wahlstrom et al., 2010b). Preclinical research indicates that the dopamine system is going through major changes in adolescence. For example, the density of D1 and D2 dopamine receptors in the striatum, firing rate of dopamine neurons, and dopamine synthesis all peak during adolescence (Teicher et al., 1995; Tarazi et al., 1999; Philpot et al., 2009; McCutcheon et al., 2012). While reports examining extracellular levels of dopamine in the striatum show both lower and higher levels of dopamine during adolescence (Badanich et al., 2006; Cao et al., 2007; Philpot et al., 2009), sub-second stimulated dopamine release is consistently found to be decreased in the striatum of adolescent rats (Stamford, 1989; Palm and Nylander, 2014; Pitts et al., 2020). Our lab has previously shown that the maximum concentration of evoked dopamine release is decreased in the nucleus accumbens (NAc) core of early adolescent male rats (Pitts et al., 2020), though the mechanism responsible for differentially regulating dopamine release in adolescent and adult rats remains unclear.

Since previous research from our lab revealed that the NAc core has the largest difference in stimulated dopamine release between adult and adolescent male rats (Pitts et al., 2020), we focused this report on understanding the mechanisms mediating dopamine release in that region. This is of particular interest because the NAc core is essential for regulating reward-related learning and goal-directed decision- making (Di Chiara, 2002; Saddoris et al., 2013), which are altered during adolescence. Moreover, terminal dopamine release in the striatum does not always correspond with action potentials from ventral tegmental area and substantia nigra projection neurons (Trulson, 1985; Mohebi et al., 2019). Release is also regulated by local circuitry via both homosynaptic and heterosynaptic mechanisms (see Nolan et al., 2020). Functionality of dopamine transporters and release probability (homosynaptic regulation) can both mediate stimulated dopamine release (see Ferris et al., 2013). Heterosynaptic mechanisms include neurotransmitter release from local interneurons and projection neurons, such as acetylcholine interneurons, which play a critical role in regulating local terminal dopamine release (see Cachope and Cheer, 2014; Collins and Saunders, 2020; Nolan et al., 2020). For instance, optogenetic stimulation of acetylcholine release drives terminal dopamine release independent of action potential through activation of nAChRs on dopamine terminals (Threlfell et al., 2012; Cachope et al., 2012). This local control over terminal dopamine release has important implications for how dopamine encodes salient information and drives behavior, and one or more of the regulatory mechanisms that mediate terminal dopamine release may change between adolescence and adulthood.

Extensive evidence indicates sex differences exist in the dopaminergic system and its local regulation (Kuhn, 2015; Becker, 2016; Zachry et al., 2021). Previously, we have demonstrated that female adolescent rats have significantly higher evoked dopamine release in the NAc core as well as other subregions compared to that of adolescent male rats and adult females (Pitts et al., 2020). Thus, the relationship between adolescent and adult dopamine release is opposite in females, and, therefore, either (1) the mechanisms explored here will likely not be the same for females as males, or (2) there is a secondary effect that masks this mechanism in females by altering the relationship we observe at baseline. Since these mechanisms are more than likely sexually dimorphic, we focus here on parsing out the mechanism involved in the changes seen within the adolescent and adult male dopaminergic system. Further research, some of which we are conducting, is needed to understand the relationship between male and female rats.

Given the role of local modulators in the dopamine system, variations in heterosynaptic regulation of striatal dopamine release may be responsible for the neurobiological changes seen between adolescence and adulthood. Therefore, the purpose of this study is to investigate the role of local modulators on presynaptic NAc dopamine release of adult and adolescent male rats is the mechanism responsible for driving such developmental changes. Here, we use ex vivo fast scan cyclic voltammetry (FSCV) to compare stimulated dopamine release and local circuitry regulation in the NAc core of adult and adolescent male rats. We then use microdialysis to determine the influence of other extrinsic factors in vivo in mediating developmental changes in the dopaminergic system. Enhancing our understanding of the transitional changes in dopamine regulation may shed light on the mechanisms driving changes in reward-related behaviors, and related increase in vulnerability, that are characteristic of adolescence.

Significant reorganization of the dopamine system occurs during the transitional period between adolescence and adulthood. Adolescents exhibit greater dopamine receptor levels, increased neuronal sensitivity, and altered dopamine dynamics when compared to adults (Teicher et al., 1995; Bolanos et al., 1998; Galvan, 2010). Restructuring of the dopamine system occurs in protein expression and activity that affects dopamine release or uptake. Although these transitional changes in dopamine release are implicated in a wide range of psychiatric disorders, much is unknown about the mechanisms driving these age-related differences. Thus, the goal of this study was to identify variations in NAc core stimulated dopamine release and pinpoint the mechanism for which these changes may occur in adolescent and adult male rats.

Consistent with our previous findings (Pitts et al., 2020), we showed no difference in our measure of dopamine uptake (Vmax) between adult and adolescent male rats in the NAc, suggesting the rate of dopamine uptake does not drive differences in stimulated dopamine release shown here. While the affinity of dopamine for the DAT (i.e. Km) has been shown to be different in prior publications by other groups (Walker and Kuhn, 2008), the dopamine curves we generated were optimized for measures of release and Vmax, not baseline affinity measurements (i.e. Km). Km is traditionally derived from the bottom third of the descending portion of the dopamine curve in FSCV, and electrode adsorption and other artifacts are known to occlude this outcome measure without affecting our other measures (Ferris et al., 2013). Thus, we did not quantify this measure and it remains possible that the affinity of dopamine for the DAT could be different between these groups.

Stimulation parameters were adjusted to model both tonic- and phasic-like neuronal firing across a wide range of frequencies in order to mimic physiologically relevant firing patterns. Replicating our previous findings (Pitts et al., 2020), the present study found decreased dopamine release in the NAc core of adolescent male rats. This is consistent with in vivo evidence of male adolescent rats demonstrating lower NAc dopamine release than adults. For example, high-frequency stimulations of the VTA in anesthetized rats reveal significantly greater stimulated NAc dopamine release in adult males compared to adolescent males (Walker and Kuhn, 2008). In freely moving rats, differences in dopamine release between early adolescence and adulthood appear stimuli-specific and differ in habituation over repeated exposures (Robinson et al., 2011). For example, the frequency of dopamine transients was no different between early adolescent and adult rats both at baseline and in the initial response to social interactions with other rats (Robinson et al., 2011). However, the unexpected presentation of additional stimuli across many modalities showed less frequent dopamine responses in early adolescent rats compared to the classic dopamine response of adult rats (Robinson et al., 2011). We found that decreases in stimulated dopamine release are not driven by differences in release probability within a burst. For example, the paired-pulse ratio (PPR) shows the relative magnitude of release attributed to each pulse in a single burst. This differs from electrophysiological PPR in that we are directly observing the relative release magnitude from a population of neurons (as opposed to a single cell) between pulse 1 and pulse 2. PPRs are known to be frequency dependent as we show here, but we find there are no age-related differences in the distribution of release magnitude across pulses in a single burst. Of note, we previously found the age-related relationship of dopamine release in the NAc core to be opposite in females compared to males, with higher NAc dopamine release in adolescent females as compared to adult females (Pitts et al., 2020). However, research has demonstrated that striatal dopamine release is robustly regulated by ovarian hormone regulation (Yoest et al., 2018; see Zachry et al., 2021). Given these physiological differences, our proposed mechanism may be masked, or is not representative of the female dopamine system. Thus, we focus the present studies on mechanisms underlying the male adolescent and adult dopamine system with plans to study female mechanisms of dopamine release in future work.

Given no differences in uptake rate or release probability within a burst, we shifted our focus to examining the involvement of heterosynaptic regulators, like cholinergic interneurons (CIN), on local dopamine release. We examined CIN influence on dopamine release under single pulse conditions and in the aggregate magnitude of release attributed to multiple pulses in a burst that mimics ‘tonic-like’ or ‘phasic-like’ firing conditions (i.e. not the relative release across individual pulses in a single burst as with the PPR). Acetylcholine and nAChRs are important regulators of terminal dopamine release within the striatum (see Threlfell et al., 2012; Cachope and Cheer, 2014; Collins and Saunders, 2020). Activation of CINs can cause dopamine release independent of VTA-mediated action potentials (Threlfell et al., 2012; Cachope et al., 2012), while pauses in CINs amplify the signal-to-background dopamine release by decreasing dopamine to low-frequency activity (Cragg, 2006). Furthermore, the antagonism of nAChRs has been shown to regulate dopamine release in a frequency-dependent manner, decreasing dopamine release to tonic-like stimulations, while not impacting or facilitating dopamine release to phasic-like stimulations (Rice and Cragg, 2004; Cragg, 2006). We found differences between adult and adolescent rats in modulation of NAc core dopamine release by α6- containing nAChRs, but not by α7 or non-α6 β2* nAChRs. Indeed, the application of α-Ctx (a selective α6- containing nAChRs antagonist) had a completely different effect on dopamine release in adults compared to early adolescent male rats. Namely, α-Ctx decreased dopamine release to tonic-like firing in male adults, while increasing dopamine release to stimulation frequencies that model phasic-like firing in male adolescents. A previous study from our lab using adult rats found that those rats most vulnerable to sensation seeking and markers of SUD (Siciliano et al., 2017) display a similar pattern of dopamine release to adolescent rats in the present study, particularly with respect to how α6-containing nAChRs modulated dopamine release. This is an intriguing finding and may indicate that α6-containing nAChR regulation of dopamine is a biomarker for vulnerability to SUD given that adolescence is a particularly susceptible time for sensation seeking and SUD development. Additional experiments and studies across more models of vulnerability are necessary to strengthen this comparison.

We next found that antagonists of GABAA and/or GABAB receptors applied prior to administration of α-Ctx blocked the α-Ctx-induced facilitation of dopamine release in adolescents, but not in adults. Blocking GABA receptors in adolescent rats unmasked the α-Ctx mediated decrease in dopamine release at single pulse and lower frequency stimulations that is well documented in prior literature and in the current adult rat group. This suggests that the blockade of α6-containing nAChRs in adolescent rats may have two parallel and independent mechanisms, as illustrated in Figure 5. The first is the well-documented direct blocking of α6-containing nAChRs on dopamine varicosities that decreases DA release at low-frequency stimulations (i.e. the ‘masked’ effect in adolescents but present for adults). The second, and novel mechanism through early adolescence we propose, is an α-Ctx mediated reduction in GABA control of dopamine release that disinhibits dopamine and is responsible for the increase that is specific to adolescent rats. Indeed, nAChRs are expressed on the pre-synaptic terminals of GABA interneurons in the striatum (Tepper et al., 2018) and research indicates GABAA (and possibly GABAB) receptors are located on dopamine terminals and can impact both dopamine and GABA co-release (Figure 5; Pitman et al., 2014; Melchior et al., 2015; Brodnik et al., 2019; Lopes et al., 2019; Patel et al., 2024). By applying GABA receptor antagonists prior to α-Ctx, the α-Ctx-mediated changes in dopamine are free from the influence of GABA. This is confirmed by our separate experimental finding that exogenous application of GABA prior to α-Ctx also prevents the age-related differences observed following α-Ctx alone. Thus, we propose that for early adolescent rats (Figure 5), α-Ctx blocks α6 nAChRs on GABA releasing cells to lower the influence of GABA on dopamine varicosities upon stimulation. The putative source of this GABA that expresses α6 nAChRs includes both local GABA interneurons and dopamine varicosities that co-release GABA (Patel et al., 2024). This leads to disinhibition of dopamine and the elevated levels we observe only in adolescents. This effect masks the parallel mechanism of the direct influence of acetylcholine on dopamine release via varicosities only observed in adult rats. By replacing the reduced GABA levels caused by α-Ctx directly with exogenously applied GABA, or by blocking GABA receptors, we bypass the mechanism of α-Ctx-mediated reduction in GABA and subsequent disinhibition of dopamine. Although prior research has found no difference in the density of α6-containing nAChRs in the NAc of early adolescents and adults (Doura et al., 2008), differences in localization or functionality of either α6-containing nAChRs or GABA receptors may underlie changes that create this novel multisynaptic mechanism of dopamine regulation in adolescent males.

Antagonizing GABAA or GABAB receptors, alone or together, did not impact dopamine release directly (i.e. outside of α6 nAChR modulation). In fact, prior literature on the effects of GABA antagonism on dopamine release is mixed. Some report no direct impact on dopamine release (Pitman et al., 2014). However, Patel et al., 2024 recently confirmed the presence of GABA-mediated inhibition of striatal dopamine release in male and female mice. In that study, the non-competitive antagonist of GABA_AR chloride channels (i.e. Picrotoxin) was able to increase/disinhibit dopamine in the dorsal striatum and NAc (Patel et al., 2024). Differences in methodology, such as optogenetic versus electrical stimulation of dopamine varicosities, may account for the lack of GABA_AR or GABA_BR antagonist effect in our study. Given the non-selective nature of electrically evoked dopamine release here, it is possible that additional nearby GABA sources (compared to optogenetic studies) released enough GABA to ‘outcompete’ the competitive antagonists. Since GABA antagonists were only effective in the presence of α-Ctx, we propose that α-Ctx-mediated decreases in GABA may have lowered GABA enough to unmask the effects of the GABA competitive antagonists. Finally, Brodnik et al., 2019 found that GABAA receptor regulation of dopamine release in the NAc core functions through GABAB receptor activation. It is possible that a similar mechanism of action is mediating the effects seen here, although we did not investigate varying combinations of activation vs inhibition of GABAA and GABAB receptors. However, given this lack of direct effect of GABA antagonism on dopamine release, we applied GABA on the slice to confirm the role of GABA on the α-Ctx mediated effect as discussed earlier. Overall, activation of GABA receptors using GABA alone on slice led to small, but divergent dopamine release in adolescents and adults. The mechanism for this is not known, but could be differential effects of GABA receptor sensitivity on dopamine varicosities (Brodnik et al., 2019) or on CINs (Yorgason et al., 2022). Regardless, the small effects of GABA alone on a slice in the presence of endogenous GABA are likely independent of the α6-mediated control of dopamine release explored in the present study.

Lastly, we used microdialysis in awake rats to confirm that the age-dependent differences in male dopamine release are mediated by a GABA mechanism involving α6-containing nAChRs in vivo. Indeed, the effects in vivo were consistent with expectations set by our studies in slices. First, we found that GABA tone is higher at baseline in adolescents compared to adults, which is consistent with greater inhibition of dopamine release in our study (Figure 5, top row). Moreover, infusing α-Ctx directly into the NAc altered GABA tone in an age-dependent manner as indicated by the Age X Drug Interaction. Notably, α-Ctx mediated reductions in adolescent GABA levels are comparable to adult baseline GABA levels. Thus, blocking α6 nAChRs in adolescent rats makes GABA and dopamine signaling similar to that of adult rats at baseline in both our microdialysis and FSCV studies. Further studies are needed to understand the microcircuitry mediating the α6-containing nAChR regulation of dopamine release in adolescent rats. Interestingly, one report using adult mice found that antagonizing GABAB receptors increased dopamine release when β2-containing nAChRs were antagonized (Lopes et al., 2019), indicating that GABA and nAChRs have a potentially complex and reciprocal regulation of dopamine release that we suggest here may be age/developmental stage dependent.

In conclusion, we found that stimulated dopamine release is decreased in the NAc core of early adolescent male rats. This effect is driven, in part, by multisynaptic regulation of dopamine release only in adolescent male rats, through both acetylcholine acting at α6-containing nAChRs and GABA tone. The dopamine system undergoes reorganization during adolescence (see Wahlstrom et al., 2010a; Wahlstrom et al., 2010b; Padmanabhan and Luna, 2014) and these changes are implicated in behavior as well as increased vulnerability to the development of various psychiatric disorders (Spear, 2000; Spear, 2013; Nelson et al., 2005; Wahlstrom et al., 2010a; Wahlstrom et al., 2010b). The present study gives us novel insight into age-related differences in dopamine release and its regulation, thus highlighting critical neurochemical targets that may partially underlie these behavioral changes. Examining how these systems develop in healthy individuals is imperative to our understanding of how perturbations may disrupt development and lead to certain disease states.

All data generated or analyzed for this study are available at Harvard dataverse (https://dataverse.harvard.edu/) under the title eLife_2024_Iacino_Ferris, or through the following link: https://doi.org/10.7910/DVN/8D2FJ0.

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Author details

1. Melody C Iacino

   Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4807-2308

2. Taylor A Stowe

   Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States

   Contribution

   Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Elizabeth G Pitts

   Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States

   Contribution

   Conceptualization, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

4. Lacey L Sexton

   Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States

   Contribution

   Formal analysis, Investigation, Methodology, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

5. Shannon L Macauley

   1. Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States
   2. Department of Physiology, University of Kentucky College of Medicine, Lexington, United States

   Contribution

   Conceptualization, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Mark J Ferris

   Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, United States

   Contribution

   Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   mferris@wakehealth.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0127-7955

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