Rewarding Effects of the Hallucinogen 4-AcO-DMT Administration and Withdrawal in Rats: A Challenge to the Opponent-Process Theory.

According to the opponent-process theory of drug addiction, the intake of an addictive substance initiates two processes: a rapid primary process that results in the drug's rewarding effects, and a slower opponent process that leads to the aversive motivational state of drug aftereffects. This aversive state is integral in the desire, pursuit, and maintenance of drug use, potentially leading to dependence and addiction. However, current observational and experimental evidence suggests that the administration of a 5-hydroxytryptamine receptors-type 2A (5-HT2A) agonist, while capable of inducing a positive mental state in humans, may not generate the behavioral patterns typically associated with drugs of abuse. In this study, we found that administering the 5-HT2A agonist 4-Acetoxy-N,N-dimethyltryptamine fumarate (4-AcO-DMT) did not result in place preference in male rats compared to control saline administration 24 h later, after the drug has been cleared from the organism. However, in a modified place preference test where only the acute motivational effects of the drug were evaluated (excluding withdrawal), 4-AcO-DMT was found to be rewarding. Furthermore, in another modified place preference test where only the motivational effects of drug withdrawal were evaluated (excluding the acute effects of drug administration), the 24-hour aftereffect of 5-HT2A agonist administration also resulted in a robust place preference. Therefore, while 4-AcO-DMT administration was able to induce place preference, its 24-hour aftereffect also produced a strong reward. In the counterbalanced test, this reward from the aftereffect effectively overshadowed its acute rewarding properties, which could potentially create a false impression that 4-AcO-DMT lacks motivational properties. This suggests that 5-HT2A agonist administration follows a different dynamic than that proposed by the opponent-process theory of motivation and implies that the administration of 5-HT2A agonists may lead to behavioral patterns less typical of drugs associated with addiction.

AI Conversational Agent to Improve Varenicline Adherence: Protocol for a Mixed Methods Feasibility Study.

BACKGROUND: Varenicline is a pharmacological intervention for tobacco dependence that is safe and effective in facilitating smoking cessation. Enhanced adherence to varenicline augments the probability of prolonged smoking abstinence. However, research has shown that one-third of people who use varenicline are nonadherent by the second week. There is evidence showing that behavioral support helps with medication adherence. We have designed an artificial intelligence (AI) conversational agent or health bot, called "ChatV," based on evidence of what works as well as what varenicline is, that can provide these supports. ChatV is an evidence-based, patient- and health care provider-informed health bot to improve adherence to varenicline. ChatV has been programmed to provide medication reminders, answer questions about varenicline and smoking cessation, and track medication intake and the number of cigarettes. OBJECTIVE: This study aims to explore the feasibility of the ChatV health bot, to examine if it is used as intended, and to determine the appropriateness of proceeding with a randomized controlled trial. METHODS: We will conduct a mixed methods feasibility study where we will pilot-test ChatV with 40 participants. Participants will be provided with a standard 12-week varenicline regimen and access to ChatV. Passive data collection will include adoption measures (how often participants use the chatbot, what features they used, when did they use it, etc). In addition, participants will complete questionnaires (at 1, 4, 8, and 12 weeks) assessing self-reported smoking status and varenicline adherence, as well as questions regarding the acceptability, appropriateness, and usability of the chatbot, and participate in an interview assessing acceptability, appropriateness, fidelity, and adoption. We will use "stop, amend, and go" progression criteria for pilot studies to decide if a randomized controlled trial is a reasonable next step and what modifications are required. A health equity lens will be adopted during participant recruitment and data analysis to understand and address the differences in uptake and use of this digital health solution among diverse sociodemographic groups. The taxonomy of implementation outcomes will be used to assess feasibility, that is, acceptability, appropriateness, fidelity, adoption, and usability. In addition, medication adherence and smoking cessation will be measured to assess the preliminary treatment effect. Interview data will be analyzed using the framework analysis method. RESULTS: Participant enrollment for the study will begin in January 2024. CONCLUSIONS: By using predetermined progression criteria, the results of this preliminary study will inform the determination of whether to advance toward a larger randomized controlled trial to test the effectiveness of the health bot. Additionally, this study will explore the acceptability, appropriateness, fidelity, adoption, and usability of the health bot. These insights will be instrumental in refining the intervention and the health bot. TRIAL REGISTRATION: ClinicalTrials.gov NCT05997901; https://classic.clinicaltrials.gov/ct2/show/NCT05997901. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53556.

Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state.

Brain-derived neurotrophic factor (BDNF) has been implicated in the transition from a non-dependent motivational state to a drug-dependent and drug-withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine-non-dependent to a nicotine-dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non-dependent male mice find aversive is found rewarding in chronic nicotine-treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin-receptor-kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine-dependent and nicotine-withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.

Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core.

Caffeine, the most commonly consumed psychoactive drug in the world, is readily available in dietary sources, including soft drinks, chocolate, tea and coffee. However, little is known about the neural substrates that underlie caffeine's rewarding and aversive properties and what ultimately leads us to seek or avoid caffeine consumption. Using male Wistar rats in a place conditioning procedure, we show that systemic caffeine at a low intraperitoneal dose of 2 mg/kg (or 100 µM injected directly into the rostral, but not caudal, portion of the ventral tegmental area) produced conditioned place preferences. By contrast, high doses of systemic caffeine at 10 and 30 mg/kg produced conditioned place aversions. These aversions were not recapitulated by a caffeine analog restricted to the periphery. Both caffeine reward and aversion were blocked by systemic D1-like receptor antagonism using SCH23390, while systemic D2-like receptor antagonism with eticlopride had smaller effects on caffeine motivation. Most important, we demonstrated that pharmacological blockade of dopamine receptors using α-flupenthixol injected into the nucleus accumbens shell, but not core, blocked caffeine-conditioned place preferences. Conversely, α-flupenthixol injected into the nucleus accumbens core, but not shell, blocked caffeine-conditioned place aversions. Thus, our findings reveal two dopamine-dependent and functionally dissociable mechanisms for processing caffeine motivation, which are segregated between nucleus accumbens subregions. These data provide novel evidence for the roles of the nucleus accumbens subregions in mediating approach and avoidance behaviours for caffeine.

A single administration of the hallucinogen, 4-acetoxy-dimethyltryptamine, prevents the shift to a drug-dependent state and the expression of withdrawal aversions in rodents.

Despite several studies suggesting the therapeutic use of 5-hydroxytryptamine receptors type 2A (5-HT2A ) agonists in the treatment of substance use disorders, the neurobiological basis accounting for such effects are still unknown. It has been observed that chronic exposure to drugs of abuse produces molecular and cellular adaptations in ventral tegmental area (VTA) neurons, mediated by brain-derived neurotrophic factor (BDNF). These BDNF-induced adaptations in the VTA are associated with the establishment of aversive withdrawal motivation that leads to a drug-dependent state. Growing evidence suggests that 5-HT2A receptor signaling can regulate the expression of BDNF in the brain. In this study, we observed that a single systemic or intra-VTA administration of a 5-HT2A agonist in rats and mice blocks both the aversive conditioned response to drug withdrawal and the mechanism responsible for switching from a drug-naive to a drug-dependent motivational system. Our results suggest that 5-HT2A agonists could be used as therapeutic agents to reverse a drug dependent state, as well as inhibiting the aversive effects produced by drug withdrawal.

A proposed resolution to the paradox of drug reward: Dopamine's evolution from an aversive signal to a facilitator of drug reward via negative reinforcement.

The mystery surrounding how plant neurotoxins came to possess reinforcing properties is termed the paradox of drug reward. Here we propose a resolution to this paradox whereby dopamine - which has traditionally been viewed as a signal of reward - initially signaled aversion and encouraged escape. We suggest that after being consumed, plant neurotoxins such as nicotine activated an aversive dopaminergic pathway, thereby deterring predatory herbivores. Later evolutionary events - including the development of a GABAergic system capable of modulating dopaminergic activity - led to the ability to down-regulate and 'control' this dopamine-based aversion. We speculate that this negative reinforcement system evolved so that animals could suppress aversive states such as hunger in order to attend to other internal drives (such as mating and shelter) that would result in improved organismal fitness.

BDNF signaling in the VTA links the drug-dependent state to drug withdrawal aversions.

Drug administration to avoid unpleasant drug withdrawal symptoms has been hypothesized to be a crucial factor that leads to compulsive drug-taking behavior. However, the neural relationship between the aversive motivational state produced by drug withdrawal and the development of the drug-dependent state still remains elusive. It has been observed that chronic exposure to drugs of abuse increases brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. In particular, BDNF expression is dramatically increased during drug withdrawal, which would suggest a direct connection between the aversive state of withdrawal and BDNF-induced neuronal plasticity. Using lentivirus-mediated gene transfer to locally knock down the expression of the BDNF receptor tropomyosin-receptor-kinase type B in rats and mice, we observed that chronic opiate administration activates BDNF-related neuronal plasticity in the VTA that is necessary for both the establishment of an opiate-dependent state and aversive withdrawal motivation. Our findings highlight the importance of a bivalent, plastic mechanism that drives the negative reinforcement underlying addiction.

Dopamine D1 receptors are not critical for opiate reward but can mediate opiate memory retrieval in a state-dependent manner.

Although D1 receptor knockout mice demonstrate normal morphine place preferences, antagonism of basolateral amygdala (BLA) D1 receptors only during drug-naive rat conditioning has been reported to inhibit the expression of a morphine place preference. One possible explanation for this result is state-dependent learning. That is, the omission of the intra-BLA infusion cue during testing - which acts as a potent discriminative stimulus - may have prevented the recall of a morphine-environment association and therefore, the consequent expression of a morphine place preference. To examine this possibility, we tested whether intra-BLA infusion of the D1-receptor antagonist SCH23390 during both training and testing might reveal a morphine place preference. Our results suggest that in previously drug-naive animals, D1 receptor antagonism during testing restores the opiate conditioned place preference that is normally absent when D1 receptors are blocked only during training, suggesting that BLA D1 receptors can mediate state-dependent memory retrieval.

Ventral tegmental area GABA neurons and opiate motivation.

RATIONALE: Past research has demonstrated that when an animal changes from a previously drug-naive to an opiate-dependent and withdrawn state, morphine's motivational effects are switched from a tegmental pedunculopontine nucleus (TPP)-dependent to a dopamine-dependent pathway. Interestingly, a corresponding change is observed in ventral tegmental area (VTA) GABAA receptors, which change from mediating hyperpolarization of VTA GABA neurons to mediating depolarization. OBJECTIVES: The present study investigated whether pharmacological manipulation of VTA GABAA receptor activity could directly influence the mechanisms underlying opiate motivation. RESULTS: Using an unbiased place conditioning procedure, we demonstrated that in Wistar rats, intra-VTA administration of furosemide, a Cl(-) cotransporter inhibitor, was able to promote a switch in the mechanisms underlying morphine's motivational properties, one which is normally observed only after chronic opiate exposure. This behavioral switch was prevented by intra-VTA administration of acetazolamide, an inhibitor of the bicarbonate ion-producing carbonic anhydrase enzyme. Electrophysiological recordings of mouse VTA showed that furosemide reduced the sensitivity of VTA GABA neurons to inhibition by the GABAA receptor agonist muscimol, instead increasing the firing rate of a significant subset of these GABA neurons. CONCLUSIONS: Our results suggest that the carbonic anhydrase enzyme may constitute part of a common VTA GABA neuron-based biological pathway responsible for controlling the mechanisms underlying opiate motivation, supporting the hypothesis that VTA GABAA receptor hyperpolarization or depolarization is responsible for selecting TPP- or dopamine-dependent motivational outputs, respectively.

Infusion of brain-derived neurotrophic factor into the ventral tegmental area switches the substrates mediating ethanol motivation.

Recent work has shown that infusion of brain-derived neurotrophic factor (BDNF) into the ventral tegmental area (VTA) promotes a switch in the mechanisms mediating morphine motivation, from a dopamine-independent to a dopamine-dependent pathway. Here we showed that a single infusion of intra-VTA BDNF also promoted a switch in the mechanisms mediating ethanol motivation, from a dopamine-dependent to a dopamine-independent pathway (exactly opposite to that seen with morphine). We suggest that intra-VTA BDNF, via its actions on TrkB receptors, precipitates a switch similar to that which occurs naturally when mice transit from a drug-naive, non-deprived state to a drug-deprived state. The opposite switching of the mechanisms underlying morphine and ethanol motivation by BDNF in previously non-deprived animals is consistent with their proposed actions on VTA GABAA receptors.

The neurobiology of opiate motivation.

Opiates are a highly addictive class of drugs that have been reported to possess both dopamine-dependent and dopamine-independent rewarding properties. The search for how, if at all, these distinct mechanisms of motivation are related is of great interest in drug addiction research. Recent electrophysiological, molecular, and behavioral work has greatly improved our understanding of this process. In particular, the signaling properties of GABA(A) receptors located on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to understanding the interplay between dopamine-dependent and dopamine-independent mechanisms of opiate motivation.

Adenosine A1 and A2A receptors are not upstream of caffeine's dopamine D2 receptor-dependent aversive effects and dopamine-independent rewarding effects.

Caffeine is widely consumed throughout the world, but little is known about the mechanisms underlying its rewarding and aversive properties. We show that pharmacological antagonism of dopamine not only blocks conditioned place aversion to caffeine, but also reveals dopamine blockade-induced conditioned place preferences. These aversive effects are mediated by the dopamine D(2) receptor, as knockout mice showed conditioned place preferences in response to doses of caffeine that C57Bl/6 mice found aversive. Furthermore, these aversive responses appear to be centrally mediated, as a quaternary analog of caffeine failed to produce conditioned place aversion. Although the adenosine A(2A) receptor is important for caffeine's physiological effects, this receptor seems only to modulate the appetitive and aversive effects of caffeine. A(2A) receptor knockout mice showed stronger dopamine-dependent aversive responses to caffeine than did C57Bl/6 mice, which partially obscured the dopamine-independent and A(2A) receptor-independent preferences. Additionally, the A(1) receptor, alone or in combination with the A(2A) receptor, does not seem to be important for caffeine's rewarding or aversive effects. Finally, excitotoxic lesions of the tegmental pedunculopontine nucleus revealed that this brain region is not involved in dopamine blockade-induced caffeine reward. These data provide surprising new information on the mechanism of action of caffeine, indicating that adenosine receptors do not mediate caffeine's appetitive and aversive effects. We show that caffeine has an atypical reward mechanism, independent of the dopaminergic system and the tegmental pedunculopontine nucleus, and provide additional evidence in support of a role for the dopaminergic system in aversive learning.

Dopaminergic signaling mediates the motivational response underlying the opponent process to chronic but not acute nicotine.

The mesolimbic dopamine (DA) system is implicated in the processing of the positive reinforcing effect of all drugs of abuse, including nicotine. It has been suggested that the dopaminergic system is also involved in the aversive motivational response to drug withdrawal, particularly for opiates, however, the role for dopaminergic signaling in the processing of the negative motivational properties of nicotine withdrawal is largely unknown. We hypothesized that signaling at dopaminergic receptors mediates chronic nicotine withdrawal aversions and that dopaminergic signaling would differentially mediate acute vs dependent nicotine motivation. We report that nicotine-dependent rats and mice showed conditioned place aversions to an environment paired with abstinence from chronic nicotine that were blocked by the DA receptor antagonist alpha-flupenthixol (alpha-flu) and in DA D(2) receptor knockout mice. Conversely, alpha-flu pretreatment had no effect on preferences for an environment paired with abstinence from acute nicotine. Taken together, these results suggest that dopaminergic signaling is necessary for the opponent motivational response to nicotine in dependent, but not non-dependent, rodents. Further, signaling at the DA D(2) receptor is critical in mediating withdrawal aversions in nicotine-dependent animals. We suggest that the alleviation of nicotine withdrawal primarily may be driving nicotine motivation in dependent animals.

Ventral tegmental area BDNF induces an opiate-dependent-like reward state in naive rats.

The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor (BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a dopamine-dependent opiate reward system, identical to that seen when an opiate-naïve rat becomes dependent and withdrawn. This shift involves a switch in the gamma-aminobutyric acid type A (GABAA) receptors of VTA GABAergic neurons, from inhibitory to excitatory signaling.

Different neural systems mediate morphine reward and its spontaneous withdrawal aversion.

The opponent-process theory posits that the aversive state of acute opiate withdrawal is a consequence of, and depends on, the previous rewarding state evoked by acute morphine reward. Although the brainstem tegmental pedunculopontine nucleus (TPP) is crucial for the rewarding component of morphine, the source of the later aversive component is not known. It is possible that (i) the second aversive process takes place within the TPP itself or (ii) morphine reward in the TPP activates an unconditioned opponent motivational process in another region of the brain. The effects of reversible inactivation of the TPP on the motivational properties of acute morphine and its spontaneous withdrawal effects in non-drug-dependent rats were examined using a place-conditioning paradigm. Reversible inactivation of the TPP with lidocaine or bupivacaine immediately before the morphine injection blocked the rewarding properties of morphine in non-dependent rats. Blocking the rewarding effects of morphine also blocked the opponent aversive effects of acute morphine withdrawal. In contrast, reversible inactivation of the TPP during the acute morphine withdrawal did not block this opponent aversive process. Our results confirm that the TPP is a critical neural substrate underlying the acute rewarding effects of morphine in non-dependent rats. Furthermore, the opponent aversive process of acute morphine withdrawal is induced by the acute rewarding effects of morphine. However, the TPP does not directly mediate the spontaneous withdrawal aversion (the opponent process), suggesting that a different system, triggered by the changes in the TPP after the primary drug response, produces the aversion itself.

GABA(A) receptors mediate the opposing roles of dopamine and the tegmental pedunculopontine nucleus in the motivational effects of ethanol.

Recent work has demonstrated that changes in ventral tegmental area (VTA) GABA(A) receptor ion conductance properties are responsible for switching morphine's positive reinforcing properties from a dopamine-independent to a dopamine-dependent pathway when an animal transitions from a non-deprived (minimal drug exposure) to a dependent (chronic drug exposure) and withdrawn state. Here we show that a double dissociation of ethanol's positive reinforcing properties is exactly opposite to that seen with morphine. In C57BL/6 mice, ethanol-conditioned place preferences were blocked in dopamine D2 receptor knockout non-deprived mice, but not by a lesion of the tegmental pedunculopontine nucleus (TPP). On the other hand, TPP lesions, but not a D2 receptor mutation, blocked ethanol-conditioned place preferences in ethanol-dependent and withdrawn mice. The opposite effects of ethanol and opiates can be explained by their proposed actions through a common VTA GABA(A) receptor switching mechanism.

Tegmental pedunculopontine glutamate and GABA-B synapses mediate morphine reward.

The tegmental pedunculopontine nucleus (TPP) of the midbrain is critical in mediating the acute rewarding effects of opiates. However, the circuitry and neurochemistry underlying this effect has not been determined. Here we identify TPP receptors and cell types involved in systemic morphine reward and suggest an anatomical and neurochemical model for reward in the TPP. Simple hypothetical anatomical models for serial cell arrangements and receptors in the TPP were proposed and predictions of behavioral outcome (reward or no reward) then were made, based on the administration of agonists and antagonists directly into the TPP of rats. We report that TPP-administered NMDA produced rewarding effects, although GABA agonists and antagonists had no motivational effects on their own. However, the NMDA receptor antagonist AP-7 and the GABA-B receptor antagonist saclofen, while having no motivational effects on their own, blocked systemic morphine reward as measured by conditioned place preference. These results provide positive evidence for GABA-B and glutamate synapses in the TPP, which mediates systemic morphine reward and suggest that a serial pathway for morphine reward in the TPP is unlikely.

A test of the opponent-process theory of motivation using lesions that selectively block morphine reward.

The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors.

Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits.

Methamphetamine (METH) causes dopaminergic nerve terminal degeneration and functional deficits in adult mice, but its neurodevelopmental effects are unclear. We investigated METH-initiated oxidative DNA damage in brain during the embryonic and fetal periods, and the postnatal histological and functional consequences. Pregnant CD-1 mice were treated with a single dose of METH (20 or 40 mg/kg ip) or its saline vehicle on Gestational Day 14 or 17. METH enhanced conceptal DNA oxidation, determined by 8-oxoguanine formation, in brain and liver by at least 2-fold at 1 h (P < 0.05), and more so in some fetal brains at 4 h. After birth, motor coordination on the rotarod apparatus in the METH-exposed offspring was impaired for at least 12 weeks (P < 0.05). Unlike in adults, this postnatal functional deficit in offspring exposed in utero to METH was not associated with degeneration of striatal dopaminergic nerve terminals at 12 weeks of age determined by tyrosine hydroxylase staining, suggesting a novel pathological mechanism in utero. This is the first evidence of oxidative DNA damage in embryonic and fetal brain caused by amphetamines, leading to long-term postnatal neurodevelopmental deficits via a mechanism different from that underlying the neurodegeneration observed in METH-exposed adults.