Drugs That Block Operant Conditioning

Learning is a dynamic cognitive process that can be enhanced or decreased by the function of specific drugs. In fact, all steps of the learning process, i.e., the acquisition, storage, and retrieval, have been shown to be modulated by drugs that alter cognitive function.

Thus, depending on the drug, various outcomes will occur on operant conditioning. Some drugs can enhance operant conditioning, while other drugs block it, as we will demonstrate here.

Drugs are a way to manipulate behavior and shed light on the biological mechanisms involved in learning processes. In this article, we will present various relevant studies that demonstrate how drugs can inhibit operant conditioning.

Researchers are interested in studying the relationship between drugs and operant conditioning because operant conditioning is an important learning process that shapes human behavior throughout our lives.

Operant conditioning is a strong learning method, which results in the association of an action with an outcome. It was originally described in 1938 by the psychologist B. F. Skinner, who is now considered the father of operant conditioning.^[1]

Operant conditioning can increase or decrease a specific behavior by the use of reinforcement or punishment protocols.

• A reinforcement protocol instructs that we get a reward every time we perform an action in its simplest form. As a result, we learn that we should perform this action more often. Depending on the organism, rewards range from food and sweets to social inclusion or even money.
• On the other hand, a punishment protocol instructs that we get an aversive outcome every time we perform an action. Consequently, we learn that we should avoid this action. In rodents, commonly used punishments are mild electric shocks and loud noises. In humans, characteristic examples are fines and behavioral timeouts, especially used in children.

Operant conditioning is highly relevant for our everyday lives, shaping our habits and social behavior. Thus, scientists have long tried to unravel its mysteries and understand how it can be modulated. This continuous effort has yielded a stunning number of publications, more than 20,000 according to PubMed.

Why Inhibit Operant Conditioning?

Sometimes we need to block operant conditioning because this learning process doesn’t always occur for the best. For instance, learning behavior that is ultimately destructive for ourselves or society might be a poor outcome of operant conditioning. Typical examples of destructive behaviors include drug or alcohol dependence, social isolation in autism spectrum disorder, making noise in the classroom, breaking the law, and so forth. Since these examples occur due to operant conditioning, drugs that block this learning process can be a promising intervention. In fact, research has identified several drugs that can block operant conditioning.

Why Use Drugs to Block Operant Conditioning?

Researchers are interested in using drugs to block operant conditioning to manage behavior and discover more about the underlying mechanisms.

Using drugs to block operant conditioning is not the same as implementing a learning protocol that results in the opposite result. For example, if one wants to reverse the learning effect of a positive reinforcement protocol, they could use an extinction protocol or even a punishment protocol.

To give an example, let’s say one wants to reverse a food-rewarded lever-pressing behavior in rodents. Using an extinction protocol, they would stop providing the reward, and the rodent would eventually stop pressing the lever. Using a punishment protocol, they would combine the lever-pressing with an aversive stimulus, such as a mild electric shock. Again, the rodent would eventually stop pressing the lever.

However, the temporal dynamics of these two processes are completely different. Furthermore, sometimes we want to block the learning of a behavior, rather than initiating a new protocol that will result in the “un-learning” of this behavior. We want to avoid learning in the first place. In these cases, drugs offer the best solution. This article will present various pharmacological interventions that have been shown to block operant conditioning learning in rodents.

The Dopaminergic System

Several lines of evidence support that the dopaminergic system is implicated in learning and memory. The dopaminergic system consists of the following four main pathways, namely the:

• Nigrostriatal pathway
• Mesolimbic pathway
• Mesocortical pathway
• Tuberoinfundibular pathway

The first three pathways involve projections of dopaminergic neurons from the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA) to the prefrontal cortex and striatum. The tuberoinfundibular pathway transmits dopamine from the hypothalamus to the pituitary gland via the median eminence.

Since these brain regions are involved in learning and memory, drugs that act on them will ultimately influence operant conditioning.

Dopaminergic System and the Reward System

Numerous studies have shown that the mesolimbic and nigrostriatal dopaminergic pathways are components of the brain reward system. The reward system is necessary for operant conditioning because all primary and secondary reinforcers, such as food or money, have rewarding properties.

Therefore, by using drugs to target the dopaminergic part of the reward system, researchers can better understand how the dopaminergic component of this system can modulate behavior, operant conditioning learning, and memory.

Yet, it is important to notice that several other neurons, such as GABAergic, glutamatergic and serotonergic neurons, are critical components of the rewards system. These neurons can directly or indirectly regulate the functional output of the dopaminergic neurons or act independently to code for reward, adding further levels of complexity in the brain reward system.

Operant Conditioning and the Dopaminergic System

Dopamine and its receptors, critically positioned in key brain regions, are fundamental mediators of the reward signals in the brain. Therefore, it is not surprising that drugs that alter dopaminergic neurotransmissions, such as several dopamine receptor antagonists and dopamine degrading enzymes, have been shown to block operant conditioning.

Antagonist SCH-23390

Baldwin and colleagues showed that administration of the D1 receptor antagonist SCH-23390 impaired operant learning. In their setup, rats learned to press one of the two available levers for a sucrose pellet reward. Initially, the researchers followed a continuous reinforcement protocol, but after 20 correct lever presses, they switched to a variable ratio 2 (VR2) protocol.

Rodents were divided into four experimental groups, one receiving vehicle and the other three increasing concentrations of the antagonist SCH-23390. Drug administration was performed immediately before the testing session through local microinfusion in the medial prefrontal cortex. The experimental results showed that SCH-23390 could dose-dependently impair operant learning, indicated by a reduced number of lever presses, without affecting general locomotion or food intake.^[2]

The results of this study are in accordance with previous studies showing that D1 receptor antagonism impairs both the acquisition and expression of operant conditioning learning. Several independent studies have shown that systemic administration or local infusion in the brain of SCH-23390 and other drugs with common pharmacological properties inhibit positive reinforcement appetitive learning. Thus, we can conclude that the intact function of dopaminergic neurons in several brain regions, such as the prefrontal cortex, the nucleus accumbens, and the amygdala, are indispensable for operant conditioning learning.

Catechol-O-methyltransferase (COMT)

COMT is a degradative enzyme that targets catecholamines in the brain (dopamine, epinephrine, and norepinephrine). This enzyme functions by adding a specific chemical modification to catecholamines, which results in their degradation. Thus, exogenous administration of COMT results in the  reduction of dopaminergic neurotransmission in the brain.

Taking advantage of this drug, Rapanelli and colleagues showed that local administration of recombinant COMT in the anterior cingulate cortex (ACC) of rats was able to block positive reinforcement learning, in a setup similar to the previously described one. Conversely, inhibition of endogenous COMT by entacapone (which led to an increase of dopamine levels) enhanced operant learning. These results indicate that dopamine bioavailability in the brain is an important determinant of operant conditioning learning, and manipulation of dopamine levels is sufficient to impair this process.^[3]

The Opioid System

Although the opioid system is typically studied in the context of addictive behaviors and rewards, there is evidence that it is also involved in operant conditioning and especially positive reinforcement.

Furthermore, the opioid system is implicated in dependence disorders and alcohol abuse. Several studies have assessed the potential of pharmacological modulators of the opioid receptors to block operant conditioning learning in rodents motivated by ethanol self-administration. This suggests that opioids may be an intervention for blocking addictive disorders.

The endogenous opioid system, comprised of the mu-, delta-, kappa-opioid receptors, is known to mediate the reinforcing and aversive properties of opiates, such as morphine and salvinorin. Additionally, opioid receptors are activated by neuron-released endogenous peptides, such as endorphins, enkephalins, and dynorphins. Drugs can target specific opioid receptors and lead to changes in learning.

Naloxone

In adult rats, voluntary ethanol intake can be reduced by general opioid antagonists, such as naloxone. However, Naloxone has been shown even in young rats to block ethanol-mediated positive reinforcement.^[4]

In their study, Miranda-Morales and colleagues used young rats to assess how inhibition of the opioid receptor signaling affects positive reinforcement learning. To this end, they used a nose poke apparatus that allowed for ethanol self-administration. They implemented a positive reinforcement protocol, so that every time the rodent performed a nose poke, it would receive an intraoral ethanol infusion. Positive reinforcement was achieved, as the rodents performed increasing numbers of nose pokes over time.

The results of the study showed that intraperitoneal injection of the general opioid receptor antagonist naloxone at a dose of 1mg/kg was sufficient to reduce the number of nose pokes and, consequently, ethanol uptake. Thus, naloxone blocks operant conditioning when ethanol is used as a primary reinforcer. Interestingly, similar results were obtained when sucrose was used as a reinforcer, highlighting the common molecular mechanisms that underlie the regulation of positive reinforcement learning.

Naltrindole and CTOP: Blocking specific opioid receptor subtypes

Taking into account that naloxone blocks all three opioid receptors non-selectively, the same scientific group tried to further characterize which specific opioid receptor subtype is responsible for the effect of naloxone. For this reason, Miranda-Morales and colleagues turned to subtype-specific antagonists. These drugs block the function of one opioid receptor subtype, sparing the other two.^[5]

Naltrindole is a drug that blocks only delta-opioid receptors, while CTOP is a drug that blocks only mu-opioid receptors. Again, using young rats and the above-mentioned experimental setup, the researchers showed that the delta-opioid receptor antagonist naltrindole dose-dependently impaired operant conditioning, while the mu-opioid receptor antagonist CTOP decreased operant conditioning only at the lowest dose of 0.1mg/kg.

Nor-binaltorphimine and Spiradoline

Similarly, Miranda-Morales and colleagues assessed two kappa-opioid receptor antagonists: nor-binaltorphimine and spiradoline.^[5] These two specific antagonists effectively impaired operant conditioning at the highest dose (30 mg/kg and 5 mg/kg respectively), as indicated by the reduced number of nose pokes.

The results of this study showed that specifically blocking the function of one opioid receptor, even if the other two opioid receptor subtypes are spared, is sufficient to impair operant conditioning learning. Since each specific antagonist could mimic the function of the general antagonist naloxone, the authors could not pinpoint exactly which specific opioid receptor subtype is necessary for operant conditioning. So, the authors concluded that all three opioid receptors participate in operant conditioning learning and mediate the effect of naloxone. Therefore, a fully functional opioid system is indispensable for operant conditioning with ethanol reinforcement.

The Endocannabinoid System

The endocannabinoid system is still under study, but it is thought to be crucial for both physical and cognitive functions, including operant conditioning and learning. Pharmacological methods, as well as genetic approaches, have shown that the endocannabinoid system has a neuromodulatory effect on cognitive processes. Thus, this effect may influence behavioral testing that assesses learning, including operant conditioning.

The endocannabinoid system is composed of:

• Endogenous cannabinoids: These compounds are also known as endocannabinoids. The major endocannabinoids known to date are the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
• Cannabinoid receptors: The major cannabinoid receptors are CB₁ and CB₂ which are G protein-coupled receptors. Apart from binding the endogenous cannabinoids, cannabinoid receptors are the primary targets of natural cannabinoids, such as Δ(9)-tetrahydrocannabinol (THC) and cannabidiol, which are derived from the plant cannabis.
• Biosynthetic and degradative enzymes: Enzymes are another crucial part of the endocannabinoid system. Degradative enzymes, especially the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), hold particular pharmacological interest and several specific inhibitors of these enzymes have already been developed. Inhibition of the degradative enzymes is an indirect, yet efficient way to increase the levels of endocannabinoids in the brain and enhance cannabinoid receptor-mediated neurotransmission.

The cannabinoid receptors are the most highly expressed receptors in the brain, presenting widespread localization in almost all brain structures. Specifically, both CB1 and CB2 receptors are expressed in several areas of the Reward System, such as the VTA, the nucleus accumbens (NAcc), and the prefrontal cortex (PFC). Moreover, it is accepted that the endogenous dopaminergic and endocannabinoid systems interact to regulate reward and motivation. ^[6] Thus, it makes sense to hypothesize that targeting the endocannabinoid system can affect operant conditioning learning.

THC and JZL184

In their study, Wiebelhaus and colleagues assessed the role of THC and the MAGL inhibitor JZL184 in food-mediated operant conditioning. THC is the primary psychoactive constituent of cannabis. JZL184 is a potent inhibitor of the monoacylglycerol lipase (MAGL), one of the two enzymes responsible for the degradation of endocannabinoids. Thus, both treatments upregulate cannabinoid receptor signaling in the brain.

Using a dual nose poke aperture apparatus, the researchers trained mice in a positive reinforcement operant conditioning protocol based on food rewards. During the training session, all mice were trained under a continuous reinforcement schedule, which was later changed to a fixed ratio 10 (FR10) schedule. Upon successful learning of the nose-poking task, the researchers proceeded with the testing session. The rodents were divided into groups of vehicle or drug administration, and each drug was administered prior to the testing session, allowing 30-120 minutes for the drug to work.

The experimental results indicate that both THC and JZL184 administration impaired operant conditioning learning and resulted in a reduced number of nose pokes.^[7] THC significantly lowered the number of responses per minute at dosage levels 7.5 and 10.0 mg/kg. JZL184 lowered the responses per minute at a dose of 40.0mg/kg. These changes in cognition were accompanied by reductions in spontaneous locomotor activity in the Open Field.

Thus, the disruptive effect of THC and the enzyme inhibitor JZL184 on food operant conditioning suggests that activation of CB1 receptors has a depressive effect on learning.

Cannabidiol

Moreover, another study focused on cannabidiol, the second major active constituent of cannabis. While using a conditioned place preference (CPP) readout rather than an operant conditioning protocol, they showed that cannabidiol attenuated morphine-induced CPP. This finding supports that cannabinoids reduce reward and may be considered for the treatment of addiction.^[8]

The Glutamatergic System

Glutamatergic neurotransmission is necessary for memory formation and learning.^[9]  Even though the input of the glutamatergic system in reward remained elusive for many years, it is now well understood that glutamate receptors exert an important regulatory role.

Glutamate is the major excitatory neurotransmitter in the brain, accounts for more than 70% of synaptic transmission, and interacts with many other systems. It binds to two main types of receptors: ionotropic glutamate receptors (like AMPA, NMDA, and kainate receptors) and metabotropic glutamate receptors (G-protein-coupled receptors).

Since the glutamatergic system is both abundantly represented in the brain and implicated in learning, it makes sense that drugs targeting the glutamatergic system will alter operant conditioning learning, as well. Specifically, antagonists of glutamate receptors have been assessed for their potential to block operant conditioning, as we will see in this section.

MK-801

Rapanelli and colleagues showed that intraperitoneal injection of MK-801, an antagonist of the NMDA receptor, blocked a positive reinforcement lever-pressing task in young adult rats (postnatal day 60). Three separate administration protocols were assessed. The first was acute administration of the drug 40 minutes prior to each training session. The second was a subchronic administration for 6 consecutive days before the initiation of the training period. The third protocol was the administration of the drug for 6 days during development, at postnatal days 7-11. All three experimental groups were assessed for positive reinforcement after postnatal day 60. The third administration protocol was used to evaluate if MK-801 could permanently affect brain development and learning ability in rats.

The results of the study showed that all administration schedules reduced lever pressing compared to vehicles. MK-801 results in learning deficits in the operant conditioning task, both in acute and subchronic protocols, but also if administered during the developmental period.^[10]

AP-5

Similar results were obtained by the use of another NMDA receptor antagonist, AP-5. The same scientific team performed local infusion of the drug in specific brain areas of rats, such as the anterior cingulate cortex and the striatum. Drug administration was repeated before the training or testing sessions of a positive reinforcement protocol. The experimental data indicated that NMDA receptor antagonism in the anterior cingulate cortex and the striatum impair the acquisition of lever-pressing for sucrose pellets.

Interestingly, administration of the drug prior to the testing session, once the training was successfully completed, did not elicit any learning deficits. This indicates that NMDA receptors mediate the acquisition and not the execution of the operant conditioning task. Furthermore, blocking NMDA receptors in the orbitofrontal cortex did not significantly impair operant learning. Such findings suggest that the role of NMDA receptor activation in operant learning is site-specific and subject to fine regulation.^[11]

The Cholinergic System

Acetylcholine and acetylcholine receptors (AchR) are primarily known for their role in the neuromuscular junction. However, the cholinergic system has many crucial roles in the central nervous system and, particularly, can modulate the reinforcing properties of drugs and rewards.

The regulatory function of the cholinergic system in reward stems from its interplay with both the dopaminergic and GABAergic components of the reward system. Additionally, the cholinergic system controls memory and learning, through the regulation of hippocampal plasticity.^[12] Therefore, drugs that affect the cholinergic system have been evaluated for their potential to modulate operant conditioning learning.

Scopolamine

Scopolamine is an antagonist of the muscarinic acetylcholine (mAchR) receptors that can cross the blood-brain barrier. Nisanov and colleagues showed that scopolamine blocks positive reinforcement learning in rodents. For their operant conditioning experiments, they used rats. They divided into three experimental groups, a control group, a group receiving scopolamine before the training period, and a group receiving scopolamine before the testing session.^[13]

During the initial pre-training session, all rats associated lever 1 with a light signal and lever 2 with a sound signal. Then, during the training session, the experimenters removed the levers and combined the light signal with a food reward, while the sound signal had no reward. The rodents associated the light signal with the reward and consequently the lever 1 with the reward.

In the following testing session, levers were returned to the setup, and lever-pressing behavior was scored. Rodents from all experimental groups pressed more the light-associated lever when compared to the pre-training session.

However, the group that received scopolamine before training pressed significantly less the light lever than the control. Interestingly, the group that received scopolamine after training but before testing did not present any differences compared to the control.

Such findings suggest that the intact function of the mACh receptor is necessary for the acquisition but not the expression of positive reinforcement learning. In light of this, drugs can inhibit operant conditioning and shed light on how this learning process works.

Mecamylamine

Mecamylamine is a drug that blocks nicotinic acetylcholine receptors (nAchRs) in the central and peripheral nervous systems. It has been used as a pharmacological intervention to facilitate smoking cessation in animal models and humans,  by modulating the function of the cholinergic system.

Levin and colleagues assessed the potential role of mecamylamine in the regulation of positive reinforcement in rodents.^[14] Rats were trained to press a lever to receive an intravenous administration of cocaine or gain access to food pellets, both of which acted as reinforcers for the operant conditioning task. Upon successful completion of the training, mecamylamine was injected subcutaneously at various doses (1, 2, or 4 mg/kg) before the testing session.

The experimental data showed that mecamylamine attenuated cocaine self-administration at all doses used, compared to saline. Interestingly, the two lowest doses of 1 and 2 mg/kg failed to impair food motivated operant conditioning, indicating that mecamylamine affects specific parts of the neuronal circuit that supports positive reinforcement learning. The researchers concluded that more research must be done further to elucidate the role of mecamylamine in operant conditioning.

The Serotonergic System

Previously, we discussed the role that the dopamine system plays in operant conditioning and in the reward system. However, another key system that makes operant conditioning possible is the serotonergic system. In fact, research shows that these two neurotransmitter systems interact with each other, in order to make reward learning possible.^[15]

Serotonin (5-HT) is the major neurotransmitter of the serotonergic system. The cortex has a high density of 5-HT receptors. Most of the serotonergic input in the forebrain is sent out by the dorsal raphe nuclei (DRN). The DRN are associated with promoting self-stimulation, a phenomenon that ultimately reinforces behavior through the dopaminergic system.^[15]

Currently, researchers are using optogenetic techniques and/or pharmaceutical studies to establish how the serotonergic system works with other systems. In fact, recent studies are suggesting that 5-HT may be necessary for behavioral flexibility which includes inhibiting reinforced behaviors.^[16]

Fluoxetine

Chronic use of selective reuptake inhibitors (SSRIs) is known to have therapeutic effects. But, the subsequent behavioral effects of SRRIs are not fully understood. A recent study by Sanders et al. showed that chronic fluoxetine treatment has a significant effect on food reinforced behavior. Chronic pharmacological blockade of the serotonin transporter (SERT) with fluoxetine led to a significant decrease in operant responding for reward.

Treatment with fluoxetine diminished lever pressing to a level that was comparable to that of mice that were genetically modified to not have SERT. Fluoxetine-treated mice, as well as SERT null mice, showed a significant reduction in the percentage of food that was as a result of lever pressing.

In essence, fluoxetine has the same effect as genetic deletion of SERT when it comes to blocking operant conditioning via diminishing food reward. Such findings demonstrate the importance of an intact serotonin system, specifically SERT, for achieving successful operant responding for food reward.^[17]

Citalopram

Other drugs that act on the serotonergic system also affect operant conditioning. It has been shown that acute pharmacological elevation of serotonin activity, by the use of SSRI citalopram decreases operant learning via the 5-HT2AC serotonin receptor.^[18] The use of SSRIs holds special interest to researchers since several drugs of this class are already approved by the FDA as second-generation antidepressant drugs.

It is impossible to discuss all the drugs that have been shown to compromise operant conditioning in a single article. The study of drugs that block operant conditioning is a robust area of research and has tremendous research implications. In this final part, we will just mention other interesting findings of pharmacological studies.

Not only neurotransmitters affect learning acquired through operant conditioning, enzymes and neuropeptides are also a part of the process. Thus, drugs that block operant conditioning can also be used and developed to target specific molecular components like enzymes.

Recent findings have shown that the following drugs can independently suppress operant conditioning:^[19-22]

• Cholecystokinin-octapeptide (CCK8)
• Orexin-1 receptor antagonist SB-334867
• Neurotensin receptor agonist NT69L
• Matrix metalloproteinase-9 (MMP-9) inhibitor TIMP-1

These drugs have been shown to act on neuropeptides and enzymes, ultimately influencing learning, mainly in positive reinforcement experimental paradigms. Such interactions suggest that targeting specific parts of the nervous system can noticeably alter cognition.

The list of drugs that impair operant conditioning learning is long and still expanding. Several conventional and unconventional candidates have emerged through a multitude of experimental approaches that use different setups and protocols.

It is now evident that operant learning depends on several independent but interwired neuronal circuits. Thus, identifying drugs that block operant conditioning not only provides novel candidates for therapeutic applications, but also offers critical insight into the neurobiological mechanisms that serve this process.

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