Cannabinoids regulate dopamine

To date, the evidence is still too limited to recommend cannabinoid-based interventions for CNS disorders involving dopaminergic dysregulation. Research into the effects of cannabinoids in this context is still in its early stages.¹
Nevertheless, it is becoming clear that endocannabinoids are very closely linked to the dopamine system and exert a significant influence on dopamine.

1. The Dopamine-Endocannabinoid System¶

Cannabinoids and dopamine are not only very closely linked²³ , but they even regulate each other, at least in the striatum.⁴
Many behaviors and clinical presentations that were previously considered to be caused solely by dopaminergic mechanisms can now be better explained as the consequences of interactions between the endocannabinoid and dopamine systems⁵, for example:

• Motor control / motor disorders (Parkinson’s disease, dyskinesia, dystonia)⁶⁷
• Reward⁸
• Addiction⁸
  • Endocannabinoids interact with the opioid system and the dopamine system.⁹
• goal-oriented behavior, motivation¹⁰

The endocannabinoid system interacts with dopaminergic neurons, whose cell bodies are located in the reticular formation of the midbrain (e.g., in the substantia nigra pars compacta (A9) and VTA (A10)) and axons in the forebrain (e.g., in the caudate/putamen and the nucleus accumbens/PFC complex). This influences activities such as movement and various cognitive functions.¹

The interaction between endocannabinoids and dopamine in regulating key brain functions—such as motor control, reward, and psychosis—occurs primarily in the nucleus accumbens, VTA, substantia nigra, striatum, and PFC. Motor function is controlled by the basal ganglia, which have high levels of 2-AG and AEA, along with other neurotransmitters such as GABA, glutamate, dopamine, and acetylcholine.¹¹

CB1R and dopamine receptors form postsynaptic heteromers.¹

1.1. Cannabinoids and Dopamine Regulate Motivation—Mesocortical¶

Mesocorticolimbic dopaminergic neurons regulate motivation and reward (in addition to cognitive functions, the central stress response, reinforcement-induced pleasure, and addiction).⁹

Cannabinoids influence the mesocortical dopamine system¹² and, like most addictive drugs, exert their effects by altering mesocorticolimbic dopamine transmission.¹¹³

Many areas of the brain’s reward system are rich in cannabinoid receptors, particularly CB1R.¹
Cannabinoid agonists increase mesolimbic dopaminergic activity by affecting DA receptor density, dopamine release, and dopamine metabolism.¹²¹⁴
Cannabinoids increased the firing rate of mesolimbic dopaminergic neurons in the VTA (A10).¹¹⁵
Δ9-THC¹³, as well as other CB1R agonists¹⁶, increase extracellular dopamine levels and dopaminergic neurotransmission in the shell of the nucleus accumbens.
Under certain circumstances, presynaptic CB1R receptors also appear to be capable of inhibiting dopamine release from dopaminergic neurons.¹⁷

Endocannabinoids influence various aspects of food reward, such as appetitive motivation.¹⁸ The CB1R agonists THC, anandamide, and 2-AG promote appetite and cravings.¹⁹ Cannabinoid agonists increase euphoria, reward, and emotionality, and reduce anxiety, motivation, and arousal. This is likely to occur primarily through glutamatergic and/or GABAergic projections to the nucleus accumbens, prefrontal cortex (PFC), and ventral tegmental area (VTA), where they induce dopaminergic changes.¹
Learn more about how endocannabinoids regulate appetite and food intake in this article Cannabinoids also regulate appetite and food intake via dopamine

One measure of reward modulation—and, more specifically, of the relationship between the effort required to respond and the value of a particular reward—is the progressive ratio, in which the requirements for receiving a single reward within a single session are increased exponentially until the test organism ceases to respond. The “breakpoint” is the ratio at which the test subject stops responding. The breakpoint thus measures the effort an organism is willing to expend to achieve a goal.²⁰²¹²²
Cannabinoid agonists increase the breakpoint—that is, the amount of effort that participants are willing to expend for a single reward.²³
A 2-AG degradation inhibitor, but not an AEA degradation inhibitor, increased the breakpoint.²⁴
Inhibition of 2-AG degradation in the VTA promoted reward-seeking behavior and phasic DA release.²⁴

CB1R receptors are also found on numerous other structures that regulate motivation and reward:⁹

• Hippocampus
• basolateral amygdala
• Hypothalamus

1.2. Cannabinoids and dopamine regulate choice impulsivity (delay discounting) via the nucleus accumbens¶

The devaluation of more distant rewards is a natural reaction. The more distant a reward is, the greater the degree of devaluation.
Stress leads to a preference for short-term rewards.²⁵

Phasic dopamine firing correlates positively with the magnitude of the reward and decreases hyperbolically as the reward delay increases. Dopamine release in the nucleus accumbens decreases in correlation with the length of an anticipated delay. Phasic DA release upon reward delivery is even higher for the larger reward during short- to medium-length delays and decreases with increasing delay to the level observed for the small, immediate reward.²³²⁶²⁷

Cannabinoids influence decision-making impulsivity only indirectly by modulating dopamine.²³
In intertemporal decision-making tasks, drugs that acutely increase dopamine enhance self-control and lead to a more frequent choice of the larger, delayed reward over the smaller, immediate one, whereas drugs that acutely decrease dopamine promote the impulsive choice of the smaller but immediate reward.
The CB1R agonist Δ9-THC increases self-control, while previously administered CB1R antagonists block this effect.
CB1R antagonists reduce the effects of DA agonists.²⁸
CB1R antagonists alone do not affect self-control.
Chronic elevation of dopamine caused by drugs reduces self-control.

Chronic drug exposure leads to structural changes in the mesolimbic circuits and other brain regions and neurotransmitters. Endocannabinoids are involved:²³

• in the modulation of synaptic plasticity in the VTA
• in the increase in phasic DA release following the administration of dopaminergic drugs
• in the development and formation of awareness
• in the conditioned drug search
• a relapse or resumption of drug use triggered by a cue

Participants who had been sensitized to the effects of cocaine exhibited impulsivity in their choices during intertemporal decision-making tasks.²³
While, prior to sensitization, a higher dopamine release indicates a greater reward as long as the delay is less than 10 seconds, after sensitization has occurred, the phasic release for the small immediate reward is relatively higher, regardless of the delay.²⁶
A CB1R antagonist administered prior to cocaine exposure prevented²⁶

• impulsivity in decision-making
• the maladaptive patterns of phasic dopamine release
  A CBR1 antagonist following cocaine sensitization²⁶
• reversed the changes in self-control

1.3. Cannabinoids and Dopamine Regulate Reward and Addiction—Mesolimbic¶

Mesocorticolimbic dopamine influences reward and addiction in humans.¹
Opioids, cannabinoids, psychostimulants, cocaine, alcohol, and nicotine acutely increase dopamine release in various brain regions,^{2930 31} including the mesolimbic dopamine system. CB1R receptors are required for this increase in phasic dopamine release.³² The CB1R antagonist rimonabant prevents the increased phasic dopamine release caused by the aforementioned drugs.³³³⁴³⁵

The mesolimbic system is primarily regulated by dopamine, which flows from the VTA (midbrain = meso) to the nucleus accumbens (part of the basal ganglia) and its downstream nuclei in the limbic system. In addition to these, the mPFC, amygdala, substantia nigra, globus pallidus, and hippocampus are also involved in the motivational and reinforcing effects of cannabinoids.³⁶³⁶³⁷
Signals from the mPFC and the basolateral amygdala to extracellular neurons in the nucleus accumbens shell are inhibited by cannabinoid agonists and completely suppressed by rimonabant (CB1R antagonist/inverse agonist).³⁷
CB1R receptors are found in the VTA, nucleus accumbens, striatum, and pyriform cortex³⁸, as well as in excitatory projections from subcortical structures to the nucleus bed of the stria terminalis, which in turn projects to the VTA.³⁹

Reward dependence appears to correlate with low AEA levels, whereas 2-AG showed no correlation.⁴⁰ Reward dependence, as measured by the “Reward Dependence” scale of the Three-Dimensional Personality Questionnaire (TPQ), is an individual’s dependence on signals of primarily social reward, particularly verbal signals of social recognition, social support, and current mood.

Dopamine encodes the difference between the expected and actual reward (reward prediction error).
Without the release of 2-AG from VTA dopamine neurons, it is not possible to form dopamine-based predictive associations, which are necessary for the control and initiation of reward-seeking behavior.⁴¹
Most midbrain dopamine neurons are activated when the reward is greater than predicted (positive prediction error), remain unchanged when the expectation is met, and show reduced activity when the reward is less than predicted (negative prediction error). The dopamine signal does not increase linearly with reward value and encodes formal economic utility. Addictive drugs generate, hijack, and amplify the dopamine signal for rewards and induce an exaggerated, uncontrolled dopamine effect on neural plasticity.
In the striatum, amygdala, and PFC, only subpopulations of neurons exhibit error coding of reward predictions.⁴²

1.3.1. 2-AG increases reward-seeking behavior¶

Endocannabinoids, particularly 2-AG, influence related behaviors through mesolimbic dopamine release:⁴³

• Reward-seeking
  • 2-AG is necessary for detecting the dopamine release triggered by a stimulus, which represents the value of a rewarding outcome
• Interval control
  • 2-AG modulates unique patterns of dopamine release and behavior under conditions of periodic reinforcement
• active avoidance behavior
  • The dopamine concentration triggered by a warning signal represents the value of an avoidance outcome. An interruption in 2-AG signaling reduces the DA level of the avoidance value signal and, consequently, active avoidance

2-AG reinforced reward-seeking behavior.²⁴³³
2-AG can enhance the effect of stimulus-induced dopamine release³³, for example, when 2-AG levels are increased by a MAGL inhibitor such as JZL184. The stimulus-induced dopamine transients then increase in amplitude and occur with a shorter latency.

1.3.2. AEA reduces reward-seeking behavior¶

In contrast, an increase in AEA reduces reward-seeking behavior and dopamine signaling during reward-seeking⁴⁴⁴⁵ , e.g., in a dose-dependent manner when AEA levels are increased by VDM11⁴⁶⁴⁷ , a selective AEA reuptake inhibitor⁴⁸, and AEA and 2-AG degradation inhibitors⁴⁹.

It is possible that AEA acts as a partial CB1R agonist only in the absence of 2-AG and as a competitive antagonist in the presence of 2-AG.³³ This would be consistent with the fact that AEA, in particular, is involved in mediating synaptic plasticity in several brain regions, a process that is suppressed by 2-AG.⁵⁰⁵¹

1.3.3. CB1R agonists increase reward-seeking behavior, while CB1R antagonists decrease it¶

The mesocorticolimbic pathway, as well as brain regions that influence decision-making, withdrawal symptoms, and relapse, express CB1R⁵² and CB2R⁵³.

CB1R agonists enhance conditioned place preference and increase preference for stimuli associated with ethanol and nicotine¹
The CB1R antagonist rimonabant

• reduced the rewarding effects of various addictive drugs; CB1R blockade (genetic or pharmacological) prevents the rise in dopamine levels that would otherwise be triggered by Δ9-THC, nicotine, heroin, morphine, or ethanol.¹
• significantly reduced dopamine levels and reward-seeking behavior.¹³
• was found to be helpful in the treatment of alcohol dependence and in smoking cessation.¹⁵⁴

CB1R-KO mice show¹² reduced voluntary alcohol consumption and an absence of the alcohol-induced increase in dopamine in the nucleus accumbens⁵⁵, lower morphine self-administration⁵⁶, reduced basal and absence of cocaine-induced hypermotility⁵⁷, and the absence of rewarding effects of nicotine in the conditioned place preference test⁵⁸, however, no similar responses to reinforcement by cocaine or nicotine in the self-administration paradigm⁵⁶.

1.3.4. CB2R agonists reduce, while CB2R antagonists increase reward-seeking behavior¶

CB2R receptors are also involved in addiction. β-Caryophyllene (BCP), believed to be a full CB2R agonist and possibly a PPAR ligand, prevented the behavioral changes—such as self-administration, conditioned place preference, or self-stimulation—induced by cocaine, nicotine, alcohol, or methamphetamine, such as self-administration, conditioned place preference, or self-stimulation, and in some cases even reversed them.⁵⁹
Pretreatment with the selective CB2R agonist JWH133 attenuated the cocaine- and nicotine-induced hyperactivity in WT mice.⁶⁰
Increased alcohol preference and increased alcohol consumption reduced CB2R expression in the ventral midbrain.⁶¹
The CB2R agonist JWH015 increased alcohol preference in mice exposed to chronic mild stress, while the CB2R inverse agonist AM630 prevented the development of alcohol preference.⁶¹ CB2R-KO mice (mice lacking CB2R) exhibit increased alcohol consumption, heightened motivation, and changes in relapse behavior.⁶²

TRPV1 are essential for the development of place preference and self-administration of methamphetamine.⁶³ TRPV1 appear to be involved in the release of dopamine in the nucleus accumbens triggered by pain stimuli.⁶⁴
In a case study, CBD (a TRPV1 and PPAR agonist) administered over 10 days reduced cannabis withdrawal symptoms.⁶⁵
CBD can help prevent relapses.⁶⁶

FAAH inhibitors reduced nicotine-induced activation of dopaminergic neurons, which contradicts the notion that endocannabinoids enhance the dopaminergic effects of nicotine via the CB1R. Apparently, in this case, FAAH inhibitors (also) potentiate the effects of certain N-acylethanolamines (e.g., OEA and PEA) that do not bind to CB1R but do bind to PPAR-α. Administration of OEA and PEA produced the same effect.⁶⁷

1.4. Cannabinoids and dopamine regulate motor function—via the basal ganglia¶

Endocannabinoids regulate dopaminergic neurotransmission, particularly through:⁵

• the effector sites of DA neurons in the basal ganglia
  • CB1R is highly expressed on striatal projection neurons, as well as in some fast-spiking, parvalbumin-containing interneurons^68697071
  • CB1R activation in the ventral hippocampus led to a significant increase in VTA dopamine neuron firing, which correlated with an increased perception of morphine reward³⁹

The basal ganglia, which control motor function, contain not only dopamine, GABA, glutamate, and acetylcholine, but also abundant cannabinoid components such as:¹

• High concentrations of AEA
• 2-AG in high concentrations
• CB1R, which plays a key role in motor control in healthy individuals

Cannabinoid-based medications improve movement disorders, such as:⁷²

• Parkinson’s:
  • Bradykinesia: CB1R antagonists
  • Tremor: CB1R agonists
  • slow the progression of Parkinson’s disease through their neuroprotective properties
    • CB1R agonists reduce excitotoxicity
    • CB2R agonists limit the toxicity of reactive microglia
    • Antioxidant cannabinoids reduce oxidative damage
• Huntington:
  • choreic movements: CB1R agonists / TRPV1 agonists

Cannabinoids increase the firing of dopamine neurons and synaptic dopamine release in the striatum^473741675

• not directly through activation of striatal CB1R, since the effect did not occur either in vitro in striatal tissue or in CB1R-KO mice⁷⁶
• a rather indirect regulation of the firing of striatal dopamine neurons through the activation of dopaminergic neurons at the somatodendritic level in the midbrain (substantia nigra / VTA)⁷⁷⁷⁸⁷⁹
• The midbrain dopamine neurons are also not activated directly, but rather indirectly through complex pathways⁸⁰ involving
  • terminal fields of the direct and indirect mesoaccumbens projections in the midbrain⁴
  • the mesocortical projection, including via TRPV1⁸¹
  • local GABAergic interneurons⁸²

Cannabinoids regulate dopaminergic firing via inhibitory CB1R receptors in GABAergic and glutamatergic terminals, resulting in a functional balance between excitatory and inhibitory inputs. This balance is characterized by a predominance of CB1R-GABAergic-mediated disinhibition of DA neuron activation.⁸³
In addition to the excitatory CB1R-GABA signaling pathway, cannabinoid TRPV1 agonists can increase the dopamine firing rate, likely at glutamatergic terminals (Marinelli et al., 2003, 2007). ⁸¹
While CB1R generally tends to massively increase dopamine release, 2-AG from the VTA regulates the homeostatic control of the cortical/subcortical dopamine balance and, thereby, the maintenance of appropriate neuroadaptations and goal-directed behaviors. CB1R activation by 2-AG inhibits the increase in firing and burst activity of dopamine neurons induced by stimulation of the PFC. 2-AG synthesis requires activation of metabotropic glutamate receptors.⁸⁴⁴³

Endocannabinoids locally regulate dopamine release in the nucleus accumbens.^85868733
Optogenetic stimulation of cholinergic interneurons triggered dopamine release in the nucleus accumbens.
A CB1R agonist inhibited this dopamine release.⁸⁸
Stimulation of cholinergic interneurons facilitated glutamatergic transmission via presynaptic α7-expressing nAChRs located on PFC terminals. The increased glutamate levels regulate DA release through at least several mechanisms:

• directly through the release of glutamate at AMPA receptors on the DA terminals
• indirectly, through the excitation of cholinergic interneurons and the activation of nAChRs on DA terminals.
• In the nucleus accumbens, endocannabinoid synthesis triggered by cholinergic interneurons also occurs through the facilitation of glutamate release onto NAc-MSNs, which drives eCB mobilization at CB1-receptor-expressing PFC terminals.

Endocannabinoids regulate motor activity in a dose-dependent manner:¹⁸⁹⁹⁰

• Low doses of cannabinoids stimulated motor activity
• High doses of cannabinoids reduced motor activity, leading to severe catalepsy (rigidity)
• The CB1R antagonist rimonabant blocked these motor effects

Endovanilloid and dopamine signaling systems appear to work together to regulate, among other things, motor control. ¹
Eicosanoid cannabinoids such as anandamide, AM404, or N-arachidonoyl-dopamine also bind to the vanilloid TRPV-1 receptor.⁶
TRPV1R¹

• can be found
  • on sensory neurons
  • on nigrostriatal dopaminergic neurons in the basal ganglia⁹¹
    • what a direct dopaminergic effect of endocannabinoids might mean⁹²
• act as molecular integrators of nociceptive stimuli⁹³

AEA causes hypokinesia in rats, which correlates with reduced activity of nigrostriatal dopaminergic neurons (de Lago et al., 2004). This could be due to AEA’s action on TRPV1 rather than on CB1R. AEA caused:⁹¹⁹²

• reduced urge to move
• reduced stereotypical behaviors
• reduced exploration in the field test
• increased downtime

The TRPV1 antagonist capsazepine reversed the effect of AEA
AEA reduced levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the caudate putamen. Capsazepine reversed this effect, suggesting that TRPV1 agonists reduce dopamine turnover in the basal ganglia.
AEA also reduced stimulus-induced dopamine release from nigrostriatal terminals.⁹¹

1.5. Cannabinoids and dopamine influence working memory, temporal processing, and behavioral adaptation—via the PFC¶

Moderate amounts of CB1R are found in the PFC.
Acute administration of CB1R agonists increases presynaptic dopamine release⁹⁴ and extracellular dopamine levels in the cortex.⁹⁵
Acute administration of cannabinoid agonists increases the activity of dopaminergic neurons in the VTA that project to the PFC.¹²
The PFC regulates many cognitive functions via dopaminergic pathways, including

• Working memory
• temporal organization of behavior
• Adaptation of behavioral strategies

Repeated administration of a cannabinoid agonist reduced dopamine turnover in the PFC, but not in the nucleus accumbens or the striatum; this effect persisted for 2 weeks after discontinuation.¹²⁹⁶⁹⁷

This long-term effect correlates neurochemically with hypofrontality^{4103 104} , defined as a state of reduced cerebral blood flow and decreased neuronal activity in the PFC¹⁰⁵¹⁰⁶ and an imbalance in the cortical-subcortical network, particularly with regard to dopamine, glutamate, and, in particular, acetylcholine.¹⁰⁷
Hypofrontality is also present in ADHD and is considered the cause of executive dysfunction in that condition.¹⁰⁵¹⁰⁸

CB1R antagonists regulate dopamine differently depending on the brain region. Systemic administration of CB1R antagonists significantly increases dopamine levels only in the cortex and leaves dopamine levels in the nucleus accumbens unchanged¹⁰⁹, suggesting that CB1R antagonists have anti-addictive and pro-cognitive effects.⁴
Cortical DA circuits control mesolimbic DA activation, and it is expected that an increase in DA in the prefrontal cortex will reduce DA activity in the accumbens.⁴ This ties in with the PFC-striatum dopamine seesaw that we have already mentioned several times. For more on this, see The Dopamine Seesaw Between the PFC and Subcortical Regions (Including the Striatum) in the article Interactions of dopaminergic brain regions In the section Neurotransmitters in ADHD / Dopamine in the chapter Neurological Aspects.

2. Cannabinoids regulate dopamine¶

2.1. Endocannabinoids regulate dopamine via DA neurons in the midbrain¶

Endocannabinoids regulate dopaminergic neurotransmission, particularly through:⁵

• the activity of DA neurons in the midbrain
  • CB1R agonists increase in vivo
    • the firing of DA cells in the SNc and VTA in vivo^1107779111
      • in cases of rapid desensitization due to repeated administration of cannabinoids¹¹²
      • In detail:⁷⁷
        • Cannabinoid agonists increased the firing rate of PFC pyramidal neurons that project to the VTA
        • Electrical VTA stimulation caused phasic inhibition in 79% of PFC pyramidal neurons
        • Cannabinoid agonists reversed this inhibition in 73% to 100% of the neurons tested
        • A selective CB1R antagonist administered afterward blocked the effects of the cannabinoid agonists and restored the inhibitory response to VTA stimulation
    • DA release in the nucleus accumbens in vivo¹¹³¹¹⁴
      • Cannabinoid mimetics inhibited stimulus-induced GABA-mediated inhibitory postsynaptic currents (IPSCs) in the nucleus accumbens¹¹⁵
      • Cannabinoid agonists simultaneously inhibit the increased firing rate of nucleus accumbens shell neurons caused by stimulation of the basolateral amygdala or the mPFC³⁷
    • the single-spike firing and burst rates of DA neurons in vitro⁵
    • CB1R agonists mediate presynaptic inhibition of glutamatergic transmission in dopamine neurons of the VTA²⁴
    • Activation of CBR at infralimbic glutamatergic terminals in the nucleus of the stria terminalis inhibits dopamine neurons in the VTA³⁹
  • CB1R antagonists in the VTA, PFC, or nucleus accumbens—but not in the amygdala—reduce reward-seeking behavior²⁴¹¹⁶
  • CB1R receptors either facilitate or inhibit the activity of dopamine neurons, depending on their presynaptic location
    • CB1R reduces the likelihood of neurotransmitter release, which, at GABAergic terminals, promotes dopaminergic activity by suppressing inhibitory input to GABA-A or GABA-B receptors on dopamine neurons^11711880
    • At glutamatergic synapses, CB1R suppresses the excitatory drive to AMPA or NMDA receptors on DA neurons⁸⁰
  • 2-AG:⁵
    • is synthesized by dopamine neurons via DGLα
    • is subsequently released postsynaptically by dopamine neurons
    • binds to presynaptic CB1R on
      • GABAergic terminals
      • glutamatergic terminals
    • DGLα activity is influenced by
      • increased Ca2+ influx (e.g., following iGluR signaling)
      • Gg/11-GPCR binding
        • Orexin-1 receptors¹¹⁹¹²⁰
        • Alpha-1 adrenoreceptors³⁴
        • mGluR5 glutamate receptors³⁴
        • Insulin receptors¹²¹
        • Neurotensin receptors¹²²¹²³

2.1.1. CB1R and CB2R are also found on dopaminergic neurons¶

Contrary to the previous assumption that dopamine neurons do not express CB1R¹²⁴, CB1R is also found on dopaminergic neurons in the VTA.^12512638

Furthermore, CB1R is found on neurons that express DRD1.¹²⁷
The CB1R could therefore directly influence dopamine release.¹²⁸

CB2R receptors on dopaminergic neurons have also been reported.^5360129130
A deletion of CB2R in dopamine neurons⁵³

• improved motor activity
• modulates anxiety- and depression-like behaviors
• reduced the rewarding effects of alcohol

2.2. Endocannabinoids regulate dopamine release from axonal terminals¶

Endocannabinoids regulate dopaminergic neurotransmission, particularly through dopamine release at axonal terminals:⁵¹³¹

• Endocannabinoids also regulate dopamine release through local modulation of the afferent terminal input at dopamine axon terminals
• Neurons in the striatum can synthesize endocannabinoids “on demand” and release them postsynaptically; these endocannabinoids then bind to presynaptic CB1R receptors (mostly on GABAergic or glutamatergic neurons).
• A potential source of endocannabinoid modulation is striatal cholinergic interneurons. These regulate dopamine release independently of cell body activation.¹³²¹³³ However, no CB1R receptors have been found on striatal cholinergic interneurons to date.

2.3. Endocannabinoids inhibit DAT-mediated dopamine reuptake¶

Several endocannabinoids¹³⁴, such as AEA, reduce DAT activity.¹³⁵¹³⁶ AEA significantly reduces the Vmax of DAT uptake, while causing only a slight decrease in Km.¹³⁷
Endocannabinoids also inhibit striatal adenosine reuptake¹³⁴, which, in the context of ADHD, counteracts the beneficial effects of DAT inhibition.

FAAH inhibition was replicated in the mouse striatum by stimulation of D2 dopamine receptors, but not of D1R. The D2R/D3R/D4R agonist quinpirole increased AEA levels in the dorsal striatum eightfold and simultaneously increased motor hyperactivity.¹³⁸
DAT-KO mice showed reduced AEA levels in the striatum.¹³⁹

RTI-371 is both a positive allosteric modulator of CB1R and a selective DAT inhibitor.¹⁴⁰

2.4. Endocannabinoids act on dopamine receptors¶

Endocannabinoids⁶⁹

• act on dopamine D1 receptors
  • The AEA reuptake inhibitor AM404 blocked D1R-mediated grooming
    • but not in D1R-KO mice
  • The AEA reuptake inhibitor AM404 inhibits contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists
  • The cannabinoid antagonist SR141716A enhances contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists
• act on dopamine D2 receptors
  • The AEA reuptake inhibitor AM404 blocked D2 receptor-mediated oral stereotypies

2.5. Endocannabinoids influence phasic and tonic dopamine firing¶

CB2 agonists inhibit the firing of dopamine neurons and terminal dopamine release.^{141142 143} The CB2R agonist JWH133 reduced the behavioral deficits and iron accumulation caused by the destruction of dopaminergic neurons in Parkinson’s disease model rats.¹⁴⁴

2.5.1. Cannabinoids increase phasic dopamine firing¶

When activity increases, 2-AG is synthesized “on demand” and then increases phasic dopamine release. 2-AG has little effect on tonic dopamine release.
Stimuli that enhance DA neuron firing (e.g., rewards) promote the mobilization of 2-AG and set in motion a positive feedback loop that facilitates subsequent DA function and appetitive behavior.⁵
CB1R antagonists or 2-AG synthesis inhibitors do not impair the firing of dopaminergic neurons per se¹⁴⁵ or the increase in dopamine in the nucleus accumbens per se³⁴; rather, they limit the increase in dopaminergic firing caused by behavioral changes or medications.³⁵³²
CB1R antagonists inhibit the ability of dopaminergic drugs (e.g., cannabinoids, nicotine, ethanol, cocaine, amphetamine) to cause a high phasic release of dopamine.^146131147

Exogenous cannabinoids such as THC and WIN55,212-2 increased phasic neuronal dopamine activity, the number of burst events, and the number of spikes per burst in the VTA^{33148 149} and increased extracellular dopamine in the nucleus accumbens.¹⁴⁹

2.5.2. Cannabinoids increase tonic dopamine firing¶

THC and WIN55,212-2 increase dopamine levels in the nucleus accumbens via CB1R by increasing tonic dopamine firing in the VTA.³³

2.6. 2-AG modulates the integration of intrinsic and extrinsic dopaminergic inputs¶

Dopamine neurons in the substantia nigra pars compacta, the VTA, and the retrorubral field integrate intrinsic and extrinsic inputs of sensory, motor, and cognitive information to determine the highest probability of reward.¹⁵⁰
2-AG is involved in the fine-tuning of the excitability of dopamine neurons by modulating the strength of the incoming synapses.¹⁵¹¹⁵²

2.7. The Inverted-U Effect of Endocannabinoids¶

Like catecholamines, endocannabinoids also exhibit an inverted-U mechanism of action. While moderate doses increase sexual activity and motivation, higher doses lead to reduced motivation.⁹
Study results on the effects of cannabinoids must therefore be considered in relation to the doses used in each case.

2.8. GABA signaling pathway¶

This paragraph is based primarily on the review by El Khoury et al.⁴

Under normal conditions, VTA dopamine neurons are subject to constant and significant inhibition via GABAergic inputs.³³
Endocannabinoids can inhibit GABA and thereby eliminate the GABA-mediated inhibition of VTA dopamine neurons. As a result, the VTA dopamine neurons become more active.

CB1Rs can be found

• are found in high numbers on GABAergic interneurons in the hippocampus, amygdala, and PFC.¹⁵³ Significantly fewer CB1R receptors are found on glutamatergic, dopaminergic, or cholinergic neurons than on neurons that primarily project to GABAergic targets. This demonstrates the importance of the GABAergic influence of cannabinoids. For example, the CB1R agonist WIN55,212-2 reduces GABAergic neurotransmission in vitro by an order of magnitude more than it reduces glutamatergic neurotransmission.⁴
• Moderately common in various cortical structures, particularly in superficial and deep layers, presumably on GABAergic interneurons.^{154155 156} The same applies to endocannabinoids that bind to CB1R (ARA, 2-AG, and the AEA precursor N-arachidonoyl-phosphatidylethanolamine (NArPE)).¹⁵⁷

Cannabinoid agonists from dopaminergic midbrain neurons¹³¹ inhibit GABA release via presynaptic CB1R, which in turn increases the activity of the dopaminergic neurons.¹²
The activation of⁴

• CB1R in GABAergic terminals disinhibits the network and increases glutamate
• CB1R in pyramidal neurons reduces glutamatergic activity

Because CB1R is predominantly expressed on GABAergic interneurons, cannabinoids increase the activity of pyramidal neurons in layers II and III.⁴
In layer V, the CB1R-glutamate effect predominates, which ultimately reduces selective excitatory outputs and thus leads to glutamatergic hypoactivity.⁴¹⁵⁸

The duration of CB1R-mediated plasticity is determined by different stimuli.¹⁵⁹

• Short-term inhibition of GABAergic transmission through short-term postsynaptic depolarization mediated by CB1R-induced inhibition of voltage-gated calcium channels¹⁵⁴¹⁶⁰
• Long-term disinhibition of pyramidal cells in the CA1 region of the hippocampus (eCB-dependent long-term depression, eCB-LTD) through intense, high-frequency synaptic stimulation^{161160 162} via CB1R-mediated regulation of presynaptic protein kinase A (PKA) and the phosphatase calcineurin¹⁶³¹⁶⁴ .

The disinhibition of VTA dopamine neurons by endocannabinoids can occur intrinsically or extrinsically:²³

• intrinsically, by acting on GABAergic interneurons¹⁶⁵
  • GABAergic interneurons preferentially target GABA-A receptors located on DA neurons in the VTA¹⁶⁶
    • Interneurons that target GABA-B receptors do not appear to respond to endocannabinoids¹⁶⁷
  • The GABA-A receptor antagonist bicuculline, as well as the CB1R antagonist SR141716A (rimonabant), inhibit the excitatory effects of the CB1R agonist HU-210 in vitro¹¹²
  • The CB1R agonist WIN55, 212-2 inhibits IPSCs (electrically evoked inhibitory postsynaptic currents) via the GABA-A receptor¹¹⁷
    • The CB1R antagonist rimonabant prevents this inhibition.
• extrinsically via GABAergic afferents (inputs)¹⁶⁵⁸⁰
  • GABAergic afferents preferentially target GABA-B receptors¹⁶⁶
  • The CB1R agonist WIN55,212-2 reduces the amplitude of GABAB-mediated IPSCs via CB1R
  • The origin of these VTA-GABA afferents is currently unknown. Possible explanations include:²³
    • Nucleus accumbens (mediates appetitive behavior by integrating inputs from cortical and limbic structures)⁹
      • No direct influence of CB1R on NAc MSNs:²³ The MSNs of the nucleus accumbens do not project directly into the VTA via axon terminals onto dopamine neurons (as previously assumed, which would directly inhibit dopamine activity), rather, the axons from the NAc primarily form synapses not with non-DA neurons, but with neurons that exert a rapid inhibitory effect via GABA-A receptors.¹⁶⁸ Furthermore, MSNs in the NAc do not express CB1R. In the NAc, CB1R is instead located on fast-spiking interneurons (FSI).¹⁶⁹
      • However, CB1R strongly inhibits MSNs in the NAc via FSI in the NAc that express CB1R. In addition, CB1R-FSI synapses on MSNs in the NAc undergo LTD induced by endocannabinoids.¹⁷⁰
    • ventral pallidum (involved in distinguishing between wanting, liking, and reward anticipation)¹⁷¹⁹
      • GABA projections from the ventral pallidum modulate the neuronal firing of VTA dopamine neurons in a cannabinoid-mediated manner:¹⁷²
        • Endocannabinoids in the ventral pallidum reduced the neuronal activity of VTA dopamine neurons
        • The NMDA glutamate receptor antagonist phencyclidine increased the neuronal activity of VTA dopamine neurons
    • rostromedial tegmental nucleus (important for processing both aversive and appetitive stimuli):²³¹⁷³
      • GABA projections from the RMTg modulate the neuronal firing of VTA dopamine neurons in a cannabinoid-mediated manner
      • The RMTg receives dense, mostly glutamatergic inputs from the lateral habenula (which encodes aversive stimuli) and mediates the inhibitory effect of the lateral habenula on dopamine neurons in the midbrain. The RMTg neurons that project to the VTA form inhibitory synapses, such that activation of this input via electrical stimulation inhibits DA firing.
      • CB1R agonists produce a long-lasting inhibition of the firing rate of RMTg GABA neurons by reducing the amplitude of excitatory postsynaptic currents. CB1R agonists significantly increase the paired-pulse ratio, suggesting that the CB1R agonist causes a reduction in glutamate release through activation of presynaptic receptors. The inhibition of GABA neurons in the RMTg correlates with an increase in the firing of VTA dopamine neurons.

The CB1R agonist THC activates dopamine. THC activates CB1R on GABA neurons, which in turn inactivate the GABA neurons. As a result, the GABA neurons that inhibit dopamine neurons are deactivated. As a result, the dopamine neurons are less inhibited and therefore more active.^174175148
As a result, the CB1R agonist THC increases dopamine levels in the nucleus accumbens. Adenosine A2A receptor antagonists (e.g., caffeine) counteract this effect.¹⁷⁶
Pretreatment with the cannabinoid antagonist rimonabant (SR141716A) enhanced the locomotor activation induced by dopamine agonists¹³⁸¹⁷⁷ , whereas CB1R antagonists alone did not induce any activation.
THC also acts on CB2R.¹⁷⁸
Cannabinoid agonists inhibited the effects of cocaine.¹⁷⁹
This suggests that CB1R has an inhibitory effect on motor activity.
Given this background, it seems logical that lower CB1R levels correlate with hyperactivity and impulsivity.¹⁸⁰

2.9. Glutamate signaling pathway¶

This section is based primarily on the review by El Khoury et al.⁴

Dopaminergic activity is modulated by glutamatergic projections, including those from the cortex and amygdala:¹⁸¹

• Indirect modulation inhibits dopamine release:
  • Glutamatergic inputs and dopaminergic projections converge on GABAergic striatal MSNs¹⁸²
• Direct innervation increases dopamine release
  • Cortical glutamatergic neurons project directly to VTA dopamine neurons
    The net effect of dopamine release is the sum of inhibition and enhancement.

Endocannabinoids from dopaminergic midbrain neurons¹³¹ mediate presynaptic inhibition of glutamatergic transmission in dopaminergic neurons of the VTA via the CB1R.⁵¹ CB1R activation causes a reduction in glutamate release, followed by a reduction in GABA activity, which in turn leads to an increase in the firing rate of dopaminergic neurons.¹²¹⁸³

CB1R receptors are found in glutamatergic and/or GABAergic synapses in cortical and subcortical structures.¹²
The acute increase in dopamine levels in the PFC caused by cannabinoids via the VTA is thought to occur through a prior increase in glutamate release and/or inhibition of GABA. However, this 2002 perspective still assumed that there were no CB1R receptors on dopaminergic neurons.⁹⁵

Activation of CB1R on glutamatergic neurons reduces the likelihood of glutamate release, which has several Consequences:²³

• the excitatory glutamatergic inputs to dopamine neurons are reduced⁵¹, which limits their burst firing
• The inhibitory effect of GABA on dopamine neurons is reduced
  • Glutamate binds to (presumably GluN2A-¹⁸⁴
  • Lower glutamate release thus reduces the inhibitory effects of dopamine
    Although endocannabinoids can theoretically reduce the likelihood of glutamate release, in practice this effect is limited because CB1R receptors are more common on GABAergic terminals than on glutamatergic terminals¹⁸⁵. The combined effect of reduced glutamate release and CB1R-induced activation of GABA neurons would decrease the number of tonically firing dopamine neurons, thereby increasing the likelihood of bursts once NMDA receptors are activated.¹⁸⁶¹⁸⁷ However, there are also other explanatory models.¹⁸⁸

Interactions between dopamine, cannabinoids, and glutamate influence synaptic plasticity.⁴¹⁸⁹

Dopamine regulates long-term potentiation (LTP) as well as long-term depression (LTD)¹⁸⁹ in the striatum, PFC, and VTA.
Stimulants modulate LTP and LTD in the PFC.¹⁹⁰¹⁹¹
Glutamates regulate dopamine in the soma as well as at the terminals of the VTA and substantia nigra. Inactivation of glutamatergic inputs to the VTA alters the burst firing patterns in the VTA.¹⁹²
Endocannabinoids modulate the cross-regulation of dopamine and glutamate at synapses in the striatum and cortex.⁴

In the striatum:⁴

• Dopamine receptors
  • D1R promotes striatal glutamatergic LTP^189193194
  • D1R block AEA in D1-expressing MSNs¹⁹⁵, which increases glutamate release. CB1R counteracts this by reducing glutamate presynaptically and inhibiting adenylate cyclase postsynaptically (while D1R increases these), which counteracts LTP induction.¹⁹³
  • D2R promotes striatal glutamatergic LTD^193196197
  • D2R and NMDA-NR2B form heteromers in the striatum.¹⁹⁸
  • Dopamine increases (via CB1R) the frequency of glutamatergic inputs to D1-expressing medium spiny neurons and decreases it (via CB1R) in D2-expressing MSNs.¹⁹⁹²⁰⁰
  • D2R increases the synthesis and release of AEA in the striatum.²⁰¹ When AEA binds to presynaptic CB1R on glutamatergic terminals, it reduces glutamate levels. This could contribute to corticostriatal LTD.²⁰²¹⁹³
• CB1R
  • CB1R ²⁰³ (as well as D2R²⁰⁴ ) attenuate cortical glutamate input and regulate corticostriatal LTD.¹⁹⁷
  • Alternative interpretation: CB1R receptors have the opposite effect of D2R receptors.²⁰⁵
    • Cannabinoid modulation of presynaptic glutamate release from neurons, those expressing Gi-coupled D2Rs appear to facilitate D2R-mediated inhibition, whereas CB1R activation in GABAergic terminals may counteract this inhibition.
  • The influence of CB1R appears to be stronger than that of TRPV1, which could also be due to the rapid desensitization of TRPV1²⁰⁶
• TRPV1
  • TRPV1 increases presynaptic glutamatergic transmission²⁰⁶ and promotes striatal LTD²⁰²
• Endocannabinoids promote LTD in D2-expressing MSNs by binding to postsynaptic TRPV1²⁰²

In the cortex:⁴

• Dopamine receptors
  In many cortical pyramidal neurons and interneurons, D1R and D2R are colocalized.
  • D1R activates glutamate in the cortex²⁰⁷
    • via postsynaptic intracellular Ca2+ and protein kinase A (PKA), independent of membrane depolarization
  • D2R inhibits glutamate in the cortex²⁰⁷
    • indirectly via GABAergic interneurons
    • postsynaptically via phospholipase A2, lipase C, and IP3, intracellular Ca²⁺, and inhibition of PKA
  • GABAergic interneurons modulate glutamatergic plasticity and cortical functions²⁰⁸
  • Excitatory and inhibitory neuronal activity form a dynamic balance to underpin executive functions and goal-directed behavior²⁰⁸
• interneurons
  There are several types of cortical interneurons with different functions, only some of which express CB1R.^1592094
  • CB1R receptors are found on cortical interneurons that express cholecystokinin²⁰⁸
  • Since CB1R is found on some fast-spiking (striatal)^{6869 70 71} parvalbumin-containing interneurons, its presence on cortical parvalbumin-containing interneurons is conceivable
• TRPV1
  • TRPV1 is highly expressed on pyramidal neurons in the cortex.²¹⁰
  • TRPV1 receptors are also involved in synaptic plasticity in the hippocampus²¹¹ and the striatum (see above).

Glutamate is also released from gliosomes in response to stimulation. CB1R increased this glutamate release from gliosomes, while CB2R and TRPV1 decreased it.²¹²

Cortical and subcortical glutamate circuits exhibit different binding mechanisms and, as a consequence, different effects:⁴
Subcortical thalamostriatal glutamatergic projections also terminate at corticostriatal MSN synapses.²¹³
In the striatum, cortical and subcortical projections terminate at spatially distinct synapses. At the same time, the characteristics of presynaptic glutamatergic elements differ between cortical and subcortical terminals.²¹⁴²¹⁵

• cortical glutamatergic synaptic terminals:
  • VGLUT1- ²¹³ s (changes have long-term effects)
  • Less than 5% express mGluR1a ²¹⁶ e (binding has an acute effect)
• subcortical, particularly thalamic, glutamatergic terminals:
  • VGLUT2- ²¹³ s (changes have long-term effects)
  • More than 50% express mGluR1a ²¹⁶ (binding has an acute effect)

CB1R receptors are found in the striatum on the terminals of both cortical (VGLUT1-positive) and subcortical (VGLUT2-positive) axons.⁷⁶
Presynaptic D2R receptors on corticostriatal terminals (VGLUT1-positive) inhibit inputs from the cortex without affecting the VGLUT2-positive inputs from glutamatergic afferents originating in the ventral subiculum.²²⁷

Endocannabinoids mediate LTD in the striatum²²⁸ as well as in the cortex²²⁹ via mGluR5 activation.
Group I and II mGluRs, such as D1R and D2R, trigger LTD in the cortex via mitogen-activated protein kinases (MAP-K). mGluR activation combined with a strong dopamine input had a synergistic effect.²³⁰²³¹
Acute cocaine administration inhibits endocannabinoid-mediated LTD by reducing the surface expression of the functional mGluR5 receptor complex, possibly via D1R.²³²
Acute THC administration also inhibits endocannabinoid-mediated LTD. This inhibition can be reversed by activating mGluR2/mGluR3 in corticostriatal glutamatergic terminals (where these receptors are co-expressed).²³³

Endocannabinoids, dopamine, and mGluR5 receptors appear to need to work together to ensure optimal synaptic plasticity
The plasticity of inhibitory transmission in the PFC (I-LTD) is regulated by endocannabinoids via mGluR5 activation and facilitated by D2R transactivation.³²³⁴
VTA-D2R, in conjunction with Group I mGluRs (mGluR1, mGluR5), induced endocannabinoid-mediated LTD and I-LTD at excitatory glutamatergic and inhibitory GABAergic synapses.²³⁴

2.10. Stimulants regulate dopamine via endocannabinoids¶

Amphetamine increases dopamine levels in the nucleus accumbens via an action-potential-dependent mechanism that is modulated by endocannabinoids.³⁵
Stimulants such as cocaine^{235119 34} and nicotine ²³⁶ trigger 2-AG synthesis in the VTA. This suppresses GABAergic input, which disinhibits dopamine neurons.⁵
The CB1 receptor antagonist rimonabant and the CB2 receptor agonist JWH133 prevented cocaine-induced hyperkinesia.²³⁷
CB1R-knockout mice do not exhibit behavioral stimulation in response to amphetamines.²³⁸

The TRPV1 agonist capsaicin increased the firing rate of VTA dopamine neurons in a dose-dependent manner and triggered bursts in just under half of them. This was mediated by enhanced glutamatergic transmission. As a consequence, pain-stimulus-dependent dopamine release in the nucleus accumbens also increased.⁶⁴

Methylphenidate and the increase in dopamine induced by MPH reduced AEA and 2-AG levels in the limbic forebrain of mice.¹⁹⁵

3. Dopamine regulates endocannabinoids¶

Intense neuronal activity leads to the synthesis and release of endocannabinoids. During phasic dopamine bursts, which release significant amounts of dopamine, endocannabinoids are produced by activated enzymes (e.g., DAGL, NAPE) and subsequently released into the extracellular space via passive diffusion through the cell membrane.⁴³

Dopamine neurons in the midbrain⁹

• synthesize endocannabinoids
• release endocannabinoids⁵¹
• have CB1R receptors on their own axon terminals
• break down endocannabinoids and endocannabinoid-related compounds

Dopamine appears to increase the release of endocannabinoids via D2 receptors, which subsequently bind retrogradely to the CB1R

• in the VTA⁵¹
• in the striatum (elevated AEA)²⁰¹¹³⁸
• Levodopa caused an increase in AEA in the basal ganglia via D1R and D2R. In rats with dopaminergic and noradrenergic neurons destroyed by 6-OHDA, levodopa did not alter endocannabinoid levels.²³⁹

AEA, in turn, inhibits the reactions mediated by D2R.²⁴⁰

4. Endocannabinoid-Dopamine-Adenosine Interaction¶

The D2 agonist quinpirole induces hyperlocomotion. This effect is inhibited by CB1R agonists. The inhibition of CB1R was blocked by the A2AR antagonist MSX-3 as well as by the CB1R antagonist rimonabant.²⁴¹
CB1R in the caudate and putamen form heteromers with adenosine A2A receptors. CB1R-mediated motor inhibition in the striatum is entirely dependent on the activation of A2AR (in the form of CB1R-ADA2 heteromers) and is reversed by A2AR antagonists. This interaction could be regulated by CB1R-D2R-A2AR heteromultimers.²⁴¹

5. Endocannabinoids regulate synaptic plasticity¶

General Information on Synaptic Plasticity at Synaptic Plasticity: Learning and Unlearning in the article “Neurological Foundations.”

5.1. Short-term plasticity¶

5.1.1. Depolarization induces suppression of inhibition (DSI) or excitation (DSE)¶

Depolarization caused by strong activation (repeated action potentials or a step depolarization) induces a temporary suppression of inhibition (DSI) or excitation (DSE) in many neurons.²⁴²
This inhibition suppression lasts for several dozen seconds.
Endocannabinoids, particularly 2-AG, are an important retrograde neurotransmitter for DSI and DSE in the hippocampus, cerebellum, and other brain regions.²⁴² The sex-dependent differences in DSI strength in Lister Hood rats did not result from the number or function of CB1R receptors (activated by 2-AG), but rather from tonic 2-AG signaling.²⁴³
Endocannabinoids regulate DSI to a greater extent than DSE.²⁴³

5.1.2. Metabotropic-induced suppression of inhibition (MSI) or excitation (MSE)¶

Metabotropic (via a metabolic process) suppression of inhibition (MSI) or excitation (MSE) are forms of synaptic short-term plasticity.²⁴²

Endocannabinoids induce MSI/MSE following the activation of a postsynaptic Gq/11-coupled GPCR and the activation of phospholipase Cβ. Phospholipase C produces diacylglycerol. This is deacylated by diacylglycerol lipase to form 2-AG. The 2-AG diffuses toward the presynapse and binds to CB1R there, which inhibits synaptic transmission.¹⁵⁴
The calcium sensitivity of PLCβ1 leads to a synergistic interaction between DSI/DSE and MSI/MSE.²⁴²

5.2. Long-term plasticity¶

5.2.1. Long-Term Potentiation (LTP)¶

Long-term potentiation (LTP) is a universal form of long-lasting strengthening of synaptic connections.

5.2.2. Long-Term Depression (LTD)¶

Long-term depression (LTD) is a universal form of long-lasting reduction in synaptic connections.
There are two types of LTD: homosynaptic LTD and heterosynaptic LTD. For an introduction to this topic, see Synaptic Plasticity: Learning and Unlearning in the article “Neurological Basics.”

Endocannabinoids can induce homosynaptic, heterosynaptic, or autaptic LTD.²⁴²²⁴⁴ Heterosynaptic LTD induced by endocannabinoids at inhibitory synapses in the hippocampus appears to require inhibition of adenylyl cyclase and the involvement of the presynaptic proteins RIM1α and RAB3B. Endocannabinoid-mediated LTD at inhibitory synapses increases dendritic excitability, which enhances excitatory transmission within a narrow spatial range.
Endocannabinoid-mediated LTD appears to be involved in the maturation of cortical circuits and may occur with or without the involvement of CB1R.{Lu HC, Mackie K (2016): An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. April 1, 2016;79(7):516-25. doi: 10.1016/j.biopsych.2015.07.028. PMID: 26698193; PMCID: PMC4789136. REVIEW}}
According to other reports, CB1R in glutamatergic terminals of the PFC that project to the NAc are essential for LTD.²⁴⁵ CB1R-KO mice showed no LTD at corticostriatal synapses¹⁹⁷ and exhibit impaired habit formation and increased exploratory behavior.²⁴⁶ Similarly, FOXP2 is required for LTD, and FOXP2-KO mice and blackbirds exhibit disorders in LTD and learning.²⁴⁵ Both CB1R and FOXP2 are candidate genes for ADHD.
Autaptic LTD: Autaptic neurons exhibit both endocannabinoid-mediated DSE and MSE. Autaptic LTD is CB1R-dependent; however, it is induced not via the G(i/o) or G(s) proteins typically activated by CB1R, but rather via G(q) proteins.²⁴⁴

5.2.3. Slow Self-Inhibition (SSI)¶

Slow self-inhibition (SSI) is a process that suppresses neuronal excitability. SSI occurs primarily in low-threshold spiking cortical interneurons and cerebellar basket cells, but also in some cortical principal cells.²⁴²
Endocannabinoids, particularly the synthesis of 2-AG during intense neuronal stimulation, lead to the activation of somatic CB1R and a somatic potassium current—likely an inward-directed potassium channel—and result in an SSI.²⁴⁷²⁴⁸