Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.

Opioid drugs are a first-line treatment for severe acute pain and other chronic pain conditions, but long-term opioid drug use produces opioid-induced hyperalgesia (OIH). Co-administration of cannabinoids with opioid receptor agonists produce anti-nociceptive synergy, but cannabinoid receptor agonists may also produce undesirable side effects. Therefore, positive allosteric modulators (PAM) of cannabinoid type-1 receptors (CB1R) may provide an option reducing pain and/or enhancing the anti-hyperalgesic effects of opioids without the side effects, tolerance, and dependence observed with the use of ligands that target the orthosteric binding sites. This study tested GAT211, a PAM of cannabinoid type-1 receptors (CB1R), for its ability to enhance the anti-hyperalgesic effects of the mu-opioid receptor (MOR) agonist DAMGO in rats treated chronically with morphine (or saline) and tested during withdrawal. We tested the effects of intra-periaqueductal gray (PAG) injections of (1) DAMGO, (2) GAT211, or (3) DAMGO + GAT211 on thermal nociception in chronic morphine-treated rats that were hyperalgesic and also in saline-treated control rats. We used slice electrophysiology to test the effects of DAMGO/GAT211 bath application on synaptic transmission in the vlPAG. Intra-PAG DAMGO infusions dose-dependently reversed chronic morphine-induced hyperalgesia, but intra-PAG GAT211 did not alter nociception at the doses we tested. When co-administered into the PAG, GAT211 antagonized the anti-nociceptive effects of DAMGO in morphine-withdrawn rats. DAMGO suppressed synaptic inhibition in the vlPAG of brain slices taken from saline- and morphine-treated rats, and GAT211 attenuated DAMGO-induced suppression of synaptic inhibition in vlPAG neurons via actions at CB1R. These findings show that positive allosteric modulation of CB1R antagonizes the behavioral and cellular effects of a MOR agonist in the PAG of rats.

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis.

Despite substantial evidence for sex differences in addiction epidemiology, addiction-relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction.

Crayfish Self-Administer Amphetamine in a Spatially Contingent Task.

Natural reward is an essential element of any organism's ability to adapt to environmental variation. Its underlying circuits and mechanisms guide the learning process as they help associate an event, or cue, with the perception of an outcome's value. More generally, natural reward serves as the fundamental generator of all motivated behavior. Addictive plant alkaloids are able to activate this circuitry in taxa ranging from planaria to humans. With modularly organized nervous systems and confirmed vulnerabilities to human drugs of abuse, crayfish have recently emerged as a compelling model for the study of the addiction cycle, including psychostimulant effects, sensitization, withdrawal, reinstatement, and drug reward in conditioned place preference paradigms. Here we extend this work with the demonstration of a spatially contingent, operant drug self-administration paradigm for amphetamine. When the animal enters a quadrant of the arena with a particular textured substrate, a computer-based control system delivers amphetamine through an indwelling fine-bore cannula. Resulting reward strength, dose-response, and the time course of operant conditioning were assessed. Individuals experiencing the drug contingent on their behavior, displayed enhanced rates of operant responses compared to that of their yoked (non-contingent) counterparts. Application of amphetamine near the supra-esophageal ganglion elicited stronger and more robust increases in operant responding than did systemic infusions. This work demonstrates automated implementation of a spatially contingent self-administration paradigm in crayfish, which provides a powerful tool to explore comparative perspectives in drug-sensitive reward, the mechanisms of learning underlying the addictive cycle, and phylogenetically conserved vulnerabilities to psychostimulant compounds.

Compulsive sucrose- and cocaine-seeking behaviors in male and female Wistar rats.

RATIONALE: Compulsive cocaine use is a key feature of cocaine addiction and understanding the factors that promote the development of such a behavior will provide important insights into the mechanism of cocaine addiction and is essential for the clinical management of the disorder. OBJECTIVES: This study aimed to determine how the preexisting compulsive reward-seeking behavior is related to the development of compulsive cocaine-seeking behavior in male and female rats and the potential impact of the reward value and estrous cycle on such behaviors. METHODS: Adult male and female Wistar rats were first trained to self-administer sucrose pellets under a chained schedule, and then, the intensity-response effects of footshock punishment on sucrose SA reinforced by different values of sucrose were measured. Subsequently, the same rats went on to self-administer intravenous cocaine and the punishment intensity-response effects on cocaine SA reinforced by different doses of cocaine were similarly determined. For the female rats, the measurements were made during different phases of the estrous cycle. RESULTS: The rats showed a wide range of levels of the compulsive behaviors despite the similar training history. Surprisingly, the compulsive sucrose-seeking behavior did not predict the compulsive cocaine-seeking behavior in either sex. Increasing cocaine dose significantly increased the compulsive cocaine-seeking behavior in the female but not male rats. Estrous cycle did not have impact on the compulsive behaviors. CONCLUSION: Preexisting differences in compulsive sucrose-seeking behavior do not predict compulsive cocaine-seeking behavior. Compulsive cocaine-seeking behavior is influenced by cocaine dose but not estrous cycle in the female rats.

Drug-sensitive Reward in Crayfish: Exploring the Neural Basis of Addiction with Automated Learning Paradigms.

Results of recent work from our labs and those of others have broadened perspectives on addiction beyond a human-specific, cognitive phenomenon. Addictive plant alkaloids are defensive compounds which have arisen to counter herbivory. With insects the true targets of the coevolutionary arms race, humans may be little more than collateral damage when impacted by 'human' drugs of abuse. The present paper summarizes recent contributions, with a primary focus on our own research in crayfish, where we characterize the behavioral and neural consequences resulting from chronic and acute exposure to psychostimulant and addictive drugs. Substituted phenethylamines, like amphetamine and cocaine, exhibit a wide range of effects in crayfish with direct parallels to those described from mammalian preparations. Unconditioned effects include intoxication and psychostimulation, where repeated exposure is accompanied by tolerance and sensitization, respectively. Psychostimulants exhibit powerful reinforcing properties in conditioned place preference, subject to extinction and reinstatement. Crayfish readily self-administer amphetamines using instrumental learning approaches. With a nervous system modular and uniquely accessible to neural probing, crayfish offer unique opportunities for studying the basic biological mechanisms of drug effects, for exploring how the appetitive disposition is implemented, and for examining how this is related to the rewarding action of drugs of abuse.

Different functional domains measured by cocaine self-administration under the progressive-ratio and punishment schedules in male Wistar rats.

BACKGROUND: Current diagnosis of drug addiction like other mental disorders is based on clinical symptoms not on neural pathophysiology and consequently, does not provide useful information on the underlying pathophysiology and may impede the efforts to identify the underlying mechanisms. Identifying the functional deficits that are relevant to addiction and can be traced to the neural systems will greatly facilitate our understanding of the heterogeneity of the condition and improve future diagnosis and treatment. Cocaine addiction is characterized by the continued use despite the dire consequences, and the deficit in inhibitory control may play a key role in this process. This study aimed to develop a paradigm to measure the punishment-induced inhibitory regulation of reward-seeking behavior. METHODS: Rats were first trained to self-administer sucrose pellets under a chained schedule and then the breaking points (BPs) under the progressive-ratio schedule, and the intensity-response effects of footshock punishment on sucrose SA were measured. Subsequently, the rats went on to self-administer intravenous cocaine, and the BPs and the punishment intensity-response effects were similarly determined. RESULTS: The areas under the punishment intensity-response curves (AUCs) were calculated and used as an indicator of the sensitivity of the inhibitory system. The BPs for cocaine were not correlated with the AUCs. Furthermore, the change in the BPs for cocaine induced by changing cocaine dose did not predict the change in the AUCs. CONCLUSION: The intensity-response effects of punishment can be used to measure the function or sensitivity of the inhibitory system independent of the motivational state.

Sex Differences in the Motivational Contrast between Sucrose and Cocaine in Rats.

There are sex differences in the vulnerability to cocaine abuse and addiction. Understanding the differences is critical for developing the sex-tailored prevention and treatment strategies. Cocaine addiction is characterized by the pathological motivation for cocaine accompanied by the diminished motivation for natural rewards. Thus, the motivational impact of cocaine relative to natural rewards likely determines the attractiveness of cocaine and likely plays a role in the vulnerability to cocaine abuse and addiction. This study aimed to determine whether the relative magnitudes or contrast of the motivational impact between cocaine and sucrose is different between sexes. To this end, cocaine-naïve out bred Wistar rats were trained to self-administer sucrose pellets and the motivation for different amounts of sucrose was then determined as the breakpoints under the progressive-ratio schedule of reinforcement. Following the sucrose tests, the same rats were trained to self-administer cocaine and the motivation for different doses of cocaine was similarly measured. For the female rats, the motivation was also measured during the diestrus and proestrus/estrus, respectively, to determine the impact of the estrous cycle on the motivational effects of cocaine and sucrose. The differences between the breakpoints of cocaine and sucrose were significantly larger in the males. The enhanced motivational contrast may contribute to the increased vulnerability to recreational cocaine abuse and addiction in the males.