Dopamine-releasing Effects Research Articles

Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

(R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal1 receptor(Gal1R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use.One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.

Sodium acamprosate and calcium exert additive effects on nucleus accumbens dopamine in the rat.

Acamprosate (Campral® – calcium‐bis[N‐acetylhomotaurinate]) is one of few available pharmacotherapies for individuals suffering from alcohol use disorder. Previously, we suggested that acamprosate reduces ethanol intake by increasing dopamine in the nucleus accumbens (nAc), thereby partly substituting for alcohol's dopamine releasing effect. An experimental study suggested the calcium moiety of acamprosate to be the active component of the drug and to mediate the relapse preventing effect. The aim of the present study was to, by means of reversed in vivo microdialysis, elucidate if the dopamine elevating properties of acamprosate are mediated by N‐acetylhomotaurine or by the calcium moiety. Male rats were equipped with a microdialysis probe in the nAc and received acute local treatment with regular acamprosate (CaAcamp 0.5 mM), calcium chloride (CaCl2 0.5 mM), sodium acamprosate (NaAcamp 0.5–1 mM), the glycine receptor (GlyR) antagonist strychnine (Stry 20 μM), or vehicle. In all experiments, extracellular levels of dopamine and taurine were examined. We found that local perfusion with both CaAcamp and CaCl2 increased dopamine levels in a GlyR‐dependent manner. NaAcamp did not influence dopamine levels, but concomitant administration with CaCl2 resulted in an additive dopamine output compared to the drugs administrated alone. We also found CaAcamp and the combination of CaCl2 and NaAcamp to increase accumbal taurine levels, suggesting that CaAcamp may act indirectly on GlyRs via taurine release. The present results indicate that both N‐acetylhomotaurine and the calcium moiety of acamprosate have dopamine elevating properties within the nAc and that, in this respect, these substances are beneficial in combination.

Salmon Calcitonin Attenuates Some Behavioural Responses to Nicotine in Male Mice.

The behavioural responses to nicotine involve appetite-regulatory hormones; however, the effects of the anorexigenic hormone amylin on reward-related behaviours induced by nicotine remain to be established. Previous studies have shown that the amylinergic pathway regulates behavioural responses to alcohol, amphetamine and cocaine. Here, we evaluated the effects of salmon calcitonin (sCT), an amylin and calcitonin receptor (CTR) agonist, on nicotine-induced locomotor stimulation and sensitisation as well as dopamine release in the nucleus accumbens (NAc) shell. Moreover, we investigated the effects of sCT on the acquisition and expression of nicotine-induced reward in the conditioned place preference (CPP) paradigm. Finally, we performed Western Blot experiments in an attempt to identify the levels of the amylin receptor components CTRa, CTRb, and RAMP1 in reward-related areas of mice responding differently to repeated injections of sCT and nicotine in the locomotor sensitisation test. We found that sCT blocked nicotine’s stimulatory and dopamine-releasing effects and prevented its ability to cause locomotor sensitisation. On the other hand, sCT did not alter nicotine-induced acquisition and expression of CPP. Lastly, sCT-nicotine treated mice from the locomotor sensitisation experiment displayed higher levels of total CTR, i.e. CTRa and CTRb together, in the reward-processing laterodorsal tegmental area (LDTg) of the brain compared to mice treated with vehicle-nicotine. Overall, the present data reveal that activation of CTR or/and amylin receptors attenuates certain nicotine-induced behaviours in male mice, further contributing to the understanding of appetite-regulatory peptides in reward regulation.

Chronic cannabinoid exposure produces tolerance to the dopamine releasing effects of WIN 55,212–2 and heroin in adult male rats

Synthetic cannabinoids were introduced into recreational drug culture in 2008 and quickly became one of the most commonly abused drugs in the United States. The neurobiological consequences resulting from synthetic cannabinoid repeated exposure remain poorly understood. It is possible that a blunted dopamine (DA) response may lead drug users to consume larger quantities to compensate for this form of neurochemical tolerance. Because the endogenous cannabinoid and opioid systems exhibit considerable cross-talk and cross-tolerance frequently develops following repeated exposure to either opioids or cannabinoids, there is interest in investigating whether a history of synthetic cannabinoid exposure influences the ability of heroin to increase DA release. To test the effects of chronic cannabinoid exposure on cannabinoid- and heroin-evoked DA release, male adult rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2; WIN) using an intravenous (IV) dose escalation regimen (0.2–0.8 mg/kg IV over 9 treatments). As predicted, WIN-treated rats showed a rightward shift in the dose-response relationship across all behavioral/physiological measures when compared to vehicle-treated controls. Then, using fast-scan cyclic voltammetry to measure changes in the frequency of transient DA events in the nucleus accumbens shell of awake and freely-moving rats, it was observed that the DA releasing effects of both WIN and heroin were significantly reduced in male rats with a pharmacological history of cannabinoid exposure. These results demonstrate that repeated exposure to the synthetic cannabinoid WIN can produce tolerance to its DA releasing effects and cross-tolerance to the DA releasing effects of heroin.

Directly to the Point: Dopamine Persistently Enhances Excitability of Direct Pathway Striatal Neurons

In this issue of Neuron, Lahiri and Bevan (2020) investigate the effects of dopamine release on striatal projection neurons. Using perforated patch recordings and optogenetics, they show that dopamine release persistently enhances the intrinsic excitability of direct pathway striatal neurons.

The relationship between childhood trauma, dopamine release and dexamphetamine-induced positive psychotic symptoms: a [11C]-(+)-PHNO PET study

Childhood trauma is a risk factor for psychosis. Amphetamine increases synaptic striatal dopamine levels and can induce positive psychotic symptoms in healthy individuals and patients with schizophrenia. Socio-developmental hypotheses of psychosis propose that childhood trauma and other environmental risk factors sensitize the dopamine system to increase the risk of psychotic symptoms, but this remains to be tested in humans. We used [11C]-(+)-PHNO positron emission tomography to measure striatal dopamine-2/3 receptor (D2/3R) availability and ventral striatal dexamphetamine-induced dopamine release in healthy participants (n = 24). The relationships between dexamphetamine-induced dopamine release, dexamphetamine-induced positive psychotic symptoms using the Positive and Negative Syndrome Scale (PANSS), and childhood trauma using the Childhood Trauma Questionnaire (CTQ) were assessed using linear regression and mediation analyses, with childhood trauma as the independent variable, dexamphetamine-induced dopamine release as the mediator variable, and dexamphetamine-induced symptoms as the dependent variable. There was a significant interaction between childhood trauma and ventral striatal dopamine release in predicting dexamphetamine-induced positive psychotic symptoms (standardized β = 1.83, p = 0.003), but a mediation analysis was not significant (standardized β = −0.18, p = 0.158). There were no significant effects of dopamine release and childhood trauma on change in negative (p = 0.280) or general PANSS symptoms (p = 0.061), and there was no relationship between ventral striatal baseline D2/3R availability and positive symptoms (p = 0.368). This indicates childhood trauma and dopamine release interact to influence the induction of positive psychotic symptoms. This is not consistent with a simple sensitization hypothesis, but suggests that childhood trauma moderates the cognitive response to dopamine release to make psychotic experiences more likely.

The Triple Combination Phentermine Plus 5-HTP/Carbidopa Leads to Greater Weight Loss, With Fewer Psychomotor Side Effects Than Each Drug Alone.

Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.

Different Dopaminergic Dysfunctions Underlying Parkinsonian Akinesia and Tremor.

Although the occurrence of Parkinsonian akinesia and tremor is traditionally associated to dopaminergic degeneration, the multifaceted neural processes that cause these impairments are not fully understood. As a consequence, current dopamine medications cannot be tailored to the specific dysfunctions of patients with the result that generic drug therapies produce different effects on akinesia and tremor. This article proposes a computational model focusing on the role of dopamine impairments in the occurrence of akinesia and resting tremor. The model has three key features, to date never integrated in a single computational system: (a) an architecture constrained on the basis of the relevant known system-level anatomy of the basal ganglia-thalamo-cortical loops; (b) spiking neurons with physiologically-constrained parameters; (c) a detailed simulation of the effects of both phasic and tonic dopamine release. The model exhibits a neural dynamics compatible with that recorded in the brain of primates and humans. Moreover, it suggests that akinesia might involve both tonic and phasic dopamine dysregulations whereas resting tremor might be primarily caused by impairments involving tonic dopamine release and the responsiveness of dopamine receptors. These results could lead to develop new therapies based on a system-level view of the Parkinson's disease and targeting phasic and tonic dopamine in differential ways.

Coordination of rapid cholinergic and dopaminergic signaling in striatum during spontaneous movement.

Interplay between dopaminergic and cholinergic neuromodulation in the striatum is crucial for movement control, with prominent models proposing pro-kinetic and anti-kinetic effects of dopamine and acetylcholine release, respectively. However, the natural, movement-related signals of striatum cholinergic neurons and their relationship to simultaneous variations in dopamine signaling are unknown. Here, functional optical recordings in mice were used to establish rapid cholinergic signals in dorsal striatum during spontaneous movements. Bursts across the cholinergic population occurred at transitions between movement states and were marked by widespread network synchronization which diminished during sustained locomotion. Simultaneous cholinergic and dopaminergic recordings revealed distinct but coordinated sub-second signals, suggesting a new model where cholinergic population synchrony signals rapid changes in movement states while dopamine signals the drive to enact or sustain those states.

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

Menthol is a significant flavoring additive in tobacco products. Accumulating clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. Our previous studies demonstrated that menthol enhanced nicotine reinforcement in rats. However, it is unclear whether menthol interacts with nicotine at the neurochemical level. The present study used intracranial microdialysis to examine whether and the ways in which menthol affects nicotine-induced dopamine release in rats in the nucleus accumbens core (NAc), a terminal field of brain reward circuitry. To make comparisons with our previous work that showed an enhancing effect of menthol on nicotine self-administration behavior, male Sprague-Dawley rats were first trained in 20 daily 1-h sessions to press a lever for intravenous nicotine self-administration (15 μg/kg/infusion). Dopamine levels were then measured in the right NAc using intracranial microdialysis coupled with high-performance liquid chromatography. Five minutes before microdialysis, the rats received an intraperitoneal injection of menthol (0, 1, 2.5, and 5 mg/kg), a subcutaneous injection of nicotine (0.2 mg/kg or its vehicle), or both. Menthol alone did not affect dopamine levels in dialysates, whereas nicotine alone elevated dopamine levels. Combined nicotine and menthol administration significantly increased dopamine levels compared with nicotine alone. These data indicate a facilitating effect of menthol on nicotine-induced dopamine release in the NAc. These findings shed light on our understanding of the neurobiological mechanisms that underlie the menthol-induced enhancement of nicotine reinforcement.

Astrocytic Mechanisms Involving Kynurenic Acid Control Δ9-Tetrahydrocannabinol-Induced Increases in Glutamate Release in Brain Reward-Processing Areas.

The reinforcing effects of Δ9-tetrahydrocannabinol (THC) in rats and monkeys, and the reinforcement-related dopamine-releasing effects of THC in rats, can be attenuated by increasing endogenous levels of kynurenic acid (KYNA) through systemic administration of the kynurenine 3-monooxygenase inhibitor, Ro 61-8048. KYNA is a negative allosteric modulator of α7 nicotinic acetylcholine receptors (α7nAChRs) and is synthesized and released by astroglia, which express functional α7nAChRs and cannabinoid CB1 receptors (CB1Rs). Here, we tested whether these presumed KYNA autoreceptors (α7nAChRs) and CB1Rs regulate glutamate release. We used in vivo microdialysis and electrophysiology in rats, RNAscope in situ hybridization in brain slices, and primary culture of rat cortical astrocytes. Acute systemic administration of THC increased extracellular levels of glutamate in the nucleus accumbens shell (NAcS), ventral tegmental area (VTA), and medial prefrontal cortex (mPFC). THC also reduced extracellular levels of KYNA in the NAcS. These THC effects were prevented by administration of Ro 61-8048 or the CB1R antagonist, rimonabant. THC increased the firing activity of glutamatergic pyramidal neurons projecting from the mPFC to the NAcS or to the VTA in vivo. These effects were averted by pretreatment with Ro 61-8048. In vitro, THC elicited glutamate release from cortical astrocytes (on which we demonstrated co-localization of the CB1Rs and α7nAChR mRNAs), and this effect was prevented by KYNA and rimonabant. These results suggest a key role of astrocytes in interactions between the endocannabinoid system, kynurenine pathway, and glutamatergic neurotransmission, with ramifications for the pathophysiology and treatment of psychiatric and neurodegenerative diseases.

Structurally Related Kappa Opioid Receptor Agonists with Substantial Differential Signaling Bias: Neuroendocrine and Behavioral Effects in C57BL6 Mice.

BackgroundThe kappa opioid receptor system has been revealed as a potential pharmacotherapeutic target for the treatment of addictions to substances of abuse. Kappa opioid receptor agonists have been shown to block the rewarding and dopamine-releasing effects of psychostimulants. Recent investigations have profiled the in vivo effects of compounds biased towards G-protein-mediated signaling, with less potent arrestin-mediated signaling. The compounds studied here derive from a series of trialkylamines: N-substituted-N- phenylethyl-N-3-hydroxyphenylethyl-amine, with N-substituents including n-butyl (BPHA), methylcyclobutyl (MCBPHA), and methylcyclopentyl (MCPPHA).MethodsBPHA, MCBPHA, and MCPPHA were characterized in vitro in a kappa opioid receptor-expressing cell line in binding assays and functional assays. We also tested the compounds in C57BL6 mice, assaying incoordination with rotarod, as well as circulating levels of the neuroendocrine kappa opioid receptor biomarker, prolactin.ResultsBPHA, MCBPHA, and MCPPHA showed full kappa opioid receptor agonism for G-protein coupling compared with the reference compound U69,593. BPHA showed no measurable β-arrestin-2 recruitment, indicating that it is extremely G-protein biased. MCBPHA and MCPPHA, however, showed submaximal efficacy for recruiting β-arrestin-2. Studies in C57BL6 mice reveal that all compounds stimulate release of prolactin, consistent with dependence on G-protein signaling. MCBPHA and MCPPHA result in rotarod incoordination, whereas BPHA does not, consistent with the reported requirement of intact kappa opioid receptor/β-arrestin-2 mediated coupling for kappa opioid receptor agonist-induced rotarod incoordination.ConclusionsBPHA, MCBPHA, and MCPPHA are thus novel differentially G-protein-biased kappa opioid receptor agonists. They can be used to investigate how signaling pathways mediate kappa opioid receptor effects in vitro and in vivo and to explore the effects of candidate kappa opioid receptor-targeted pharmacotherapeutics.

Buprenophine functions as a weak dopamine releaser in the absence of heroin but blocks the dopamine releasing effects of heroin in its presence

With the rise in opioid use and opioid‐related death in modern society, it is imperative to understand how these drugs affect neural circuits, particularly those implicated in drug‐seeking and motivated behavior. Generally, all drugs of abuse are thought to increase mesolimbic dopamine concentrations through various mechanisms, and it is widely believed these fluctuations in dopamine concentrations (and subsequent hypodopaminergic states) are implicated in the acquisition, persistence, and maintenance of addiction. Here we sought to identify increases in phasic dopamine in the nucleus accumbens of rats after intravenous diacetylmorphine (heroin) administration. Then, we sought to identify the effects on phasic dopamine after buprenorphine administration, followed by subsequent heroin administration. Utilizing fast‐scan cyclic voltammetry in awake behaving animals, we administered cumulative animal‐equivalent doses based on clinical investigations that correlated subjective measures of the drug's effect to dosage in human subjects. Either heroin or buprenorphine administered alone causes large increases in dopamine transient amplitude and frequency, whereas heroin administration after buprenorphine causes a decrease in the amplitude and frequency of transients. These data suggest a modulatory effect of buprenorphine on opioid receptors in the presence of exogenous opiates.Support or Funding InformationFunding for the project was provided by NSF grant IOS‐1557755, NIH grant R03DA038734, Boettcher Young Investigator Award and NARSAD Young Investigator Award to EBO and an institutional UROP to KJP.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Functionally Distinct Dopamine Signals in Nucleus Accumbens Core and Shell in the Freely Moving Rat.

Orchestrated signaling from mesolimbic dopamine (DA) neurons is important for initiating appropriate behavior in response to salient stimuli. Thus, subpopulations of mesolimbic DA neurons show different in vitro properties and synaptic inputs depending on their specific projections to the core and shell subterritories of the nucleus accumbens (NAc). However, the functional consequence of these differences is unknown. Here we analyze and model DA dynamics in different areas of the NAc to establish the real-time DA signal. In freely behaving animals, we find that the DA signal from mesencephalic neurons projecting to the NAc shell is dominated by synchronized bursts and pauses, whereas signaling is uniform for core-projecting neurons; this difference is amplified by cocaine.

The neural substrates for the rewarding and dopamine-releasing effects of medial forebrain bundle stimulation have partially discrepant frequency responses

Midbrain dopamine neurons have long been implicated in the rewarding effect produced by electrical brain stimulation of the medial forebrain bundle (MFB). These neurons are excited trans-synaptically, but their precise role in intracranial self-stimulation (ICSS) has yet to be determined. This study assessed the hypothesis that midbrain dopamine neurons are in series with the directly stimulated substrate for self-stimulation of the MFB and either perform spatio-temporal integration of synaptic input from directly activated MFB fibers or relay the results of such integration to efferent stages of the reward circuitry. Psychometric current-frequency trade-off functions were derived from ICSS performance, and chemometric trade-off functions were derived from stimulation-induced dopamine transients in the nucleus accumbens (NAc) shell, measured by means of fast-scan cyclic voltammetry. Whereas the psychometric functions decline monotonically over a broad range of pulse frequencies and level off only at high frequencies, the chemometric functions obtained with the same rats and electrodes are either U-shaped or level off at lower pulse frequencies. This discrepancy was observed when the dopamine transients were recorded in either anesthetized or awake subjects. The lack of correspondence between the psychometric and chemometric functions is inconsistent with the hypothesis that dopamine neurons projecting to the NAc shell constitute an entire series stage of the neural circuit subserving self-stimulation of the MFB.

Effects of dexamphetamine-induced dopamine release on resting-state network connectivity in recreational amphetamine users and healthy controls.

Dexamphetamine (dAMPH) is not only used for the treatment of attention deficit hyperactivity disorder (ADHD), but also as a recreational drug. Acutely, dAMPH induces release of predominantly dopamine (DA) in the striatum, and in the cortex both DA and noradrenaline. Recent animal studies have shown that chronic dAMPH administration can induce changes in the DA system following long-term exposure, as evidenced by reductions in DA transporters, D2/3 receptors and endogenous DA levels. However, only a limited number of studies have investigated the effects of dAMPH in the human brain. We used a combination of resting-state functional magnetic resonance imaging (rs-fMRI) and [123I]IBZM single-photon emission computed tomography (SPECT) (to assess baseline D2/3 receptor binding and DA release) in 15 recreational AMPH users and 20 matched healthy controls to investigate the short-, and long-term effects of AMPH before and after an acute intravenous challenge with dAMPH. We found that acute dAMPH administration reduced functional connectivity in the cortico-striatal-thalamic network. dAMPH-induced DA release, but not DA D2/3 receptor binding, was positively associated with connectivity changes in this network. In addition, acute dAMPH reduced connectivity in default mode networks and salience-executive-networks networks in both groups. In contrast to our hypothesis, no significant group differences were found in any of the rs-fMRI networks investigated, possibly due to lack of sensitivity or compensatory mechanisms. Our findings thus support the use of ICA-based resting-state functional connectivity as a tool to investigate acute, but not chronic, alterations induced by dAMPH on dopaminergic processing in the striatum.

Pick your poison: not all opioids are created equal in the eyes of dopamine (commentary on Vander Weele et al.).

In the current issue, Vander Weele et al. (2014) provide a previously unseen characterization of opioid-induced potentiation of dopamine release in the nucleus accumbens (NAc), an effect shared by all commonly abused drugs and thought to critically contribute to drug reinforcement. This work is extremely timely as prescription opioid abuse and addiction are currently at epidemic levels. Indeed, the rise in prescription opioid abuse may be driven by an elevated prevalence of more addictive opioids. The most common opioid analgesic has traditionally been morphine, a naturally occurring alkaloid from the opium poppy plant. However, newer synthetic opioids, such as oxycodone, are gaining popularity despite (or perhaps because of) their reportedly greater abuse potential. The work by Vander Weele et al. (2014) suggests that the greater abuse potential of oxycodone may arise from its increased ability to produce changes in NAc dopamine release. Fast-scan cyclic voltammetry was used to measure real-time dopamine fluctuations in the NAc of behaving rats. These measures add opioids to the growing list of abused drugs (including ethanol, nicotine, cocaine and cannabinoids) that elicit rapid surges in NAc dopamine concentrations. Because these dopamine ‘transients’ are causally linked to reward seeking, the ability of abused drugs to give rise to these signals is an important mechanism supporting drug reinforcement. Interestingly, Vander Weele et al. (2014) found that morphine exhibits a surprisingly brief effect on dopamine transients, augmenting these signals for <1 min. In stark contrast, oxycodone elicited a stable and significant increase in the frequency of transients for the entire 15 min recording period. Additionally, state-of-the-art microdialysis simultaneously sampled the extracellular levels of 15 different neurotransmitters at 60 s intervals. These elegant measures corroborated the fast-scan cyclic voltammetry dopamine recordings and also showed that morphine, but not oxycodone, elevated extracellular GABA levels in the NAc. If this increase in GABA acts to inhibit terminal dopamine release, it could explain morphine's weak effects on dopamine transmission. The source of this GABA signal, however, remains to be identified. Moreover, this increase in GABA is paradoxical, as it has been theorized that morphine exerts its dopamine-releasing effects through μ-opioid receptor-mediated disinhibition of dopamine neurons. Based on reported differences in the abuse potential of oxycodone and morphine, and their distinct effects on dopamine release, the current findings suggest that monitoring a drug's ability to pharmacologically elicit dopamine transients could serve as an objective assay for rational drug policy, as we have postulated for cannabinoids. Alternatively, the observed differences between morphine and oxycodone may have simply arisen from their different pharmacokinetic actions. Indeed, although both drugs were administered at the same dose, oxycodone can reach brain concentrations six times that of morphine. Nonetheless, the authors state that both drugs evoked a similar maximal increase in extracellular dopamine and inhibited movement for a similar duration. Clearly, future work will need to employ more rigorous behavioral assays (such as drug self-administration) to determine whether the differential effects of morphine and oxycodone on the dynamics of dopamine release cause their different reinforcing properties.

Attention-deficit/hyperactivity disorder adversely impacts everyday functioning in chronic methamphetamine users

s / Drug and Alcohol Dependence 140 (2014) e86–e168 e165 as this is essential to develop age-appropriate and gender-sensitive prevention strategies. Financial support: The National Institute on Health 5T32DA007238-22 (Petrakis), P50DA033945 (ORWH and NIDA; McKee). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.463 Attention-deficit/hyperactivity disorder adversely impacts everyday functioning in chronic methamphetamine users Lisa C. Obermeit, J.E. Cattie, K. Bolden, M. Marquine, Erin E. Morgan, D. Franklin, I. Grant, S.P. Woods Psychiatry, University of California, San Diego, San Diego, CA, United States Aims: Methamphetamine (MA) use commonly accompanied by significant clinical disabilities, the severity which is associated with neurocognitive impairment, polysubstance use, and psychiatric comorbidity (e.g., depression). One previously unstudied psychiatric comorbidity that may be particularly relevant to real-world functional outcomes among MA users is AttentionDeficit/Hyperactivity Disorder (ADHD), which is independently associated with a wide range of problems in everyday functioning. Methods: In the current study, we evaluated 400 individuals with DSM-IV diagnoses of MA use disorders within 18 months of evaluation who completed a comprehensive neuropsychiatric and medical research battery. 21% (n=83) of the MA subjects met lifetime diagnostic criteria for ADHD (13% with current diagnoses) as determined by structured clinical interview. All participants completed self-reportmeasures of everyday functioning, including declines in instrumental activities of daily living (IADL), cognitive complaints, and employment status. Results: Separate regressions predicting the three everyday functioning outcomes from ADHD group, along with important co-factors (i.e., demographics, depression, other substance use disorders, and regency of MA use) were significant at the omnibus level (p’s < .01). Examination of individual predictors in thesemodels revealed that ADHD diagnoses were uniquely associated with greater concurrent risk of declines in IADL, elevated cognitive complaints, and unemployment (p’s < .01). Conclusions: Findings indicate that ADHD may play an important role in MA-associated disability in a wide range of real-world activities, whichmay reflect increased comorbidity burden on neurocognitive abilties, premorbid risk factors, and/or psychosocial competencies in already vulnerable chronic MA users. Efforts to screen for and treat ADHD in individuals withMA dependencemay help to improve real-world outcomes. Financial support: This research was supported by National Institutes of Health grants P01DA12065, P50DA026306, T32DA031098 and P30MH62512. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.464 Subsecond dopamine release in cannabinoid tolerance Erik B. Oleson, A. Ranganath, M. Karamsetty, J. Cheer Neurobiology and Anatomy, University of Maryland School of Medicine, Baltimore, MD, United States Aims: Cannabinoids, includingmarijuana and its synthetic analogues, are the most frequently abused class of illicit drugs in the United States. The brain’s mesolimbic dopamine system is thought to mediate the rewarding/reinforcing properties of all drugs of abuse, including cannabinoids. Although repeated cannabinoid exposure is known to produce tolerance to several behavioral and physiologicalmeasures, it remainsunclearwhether suchapharmacological history also produces tolerance to its dopamine releasing effects. Methods: Rats were treated with either vehicle or a synthetic cannabinoid (WIN55-212-2;WIN) using an escalating dosing approach (0.2–0.8mg/kg IV over 9 treatments). We then assessed whether this dosing regimen produced tolerance to a series of behavioral/physiological measures that are routinely observed when rodents are treated with WIN (i.e., tetrad test: catalepsy, hypothermia, antinociception, and spontaneous activity). Finally, we used fast-scan cyclic voltammetry to measure real-time WIN-evoked dopamine release in the nucleus accumbens in freelymoving and behaving rats. Results: WIN-treated rats showed a rightward dose effect curve shift (0.002–0.8mg/kg IV) in each behavioral/physiological measure versus vehicle treated controls. Likewise, the dopamine releasing potency of WIN was significantly reduced in the WINtreated rats when tested at the 0.2mg/kg IV dose. Conclusions: These results demonstrate that subchronic administration of the synthetic cannabinoid WIN can produce tolerance to its dopamine releasing effects. A diminished ability to increase dopamine release may contribute to the abuse of larger cannabinoid doses and quantities, thereby advancing the addiction process. Financial support: Funded by NIDA grants: R01DA015718, R01DA022340, R01DA025890, R21DA033926 (JFC); F32DA032266 (EBO). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.465 Mediators of response to sertraline vs. placebo among recently abstinent, cocaine-dependent patients Alison Oliveto1, J. Thostenson1, T.R. Kosten2, M. Mancino1 1 UAMS, Little Rock, AR, United States 2 Baylor College of Medicine, Houston, TX, United

5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: A comparative study using in vivo microdialysis

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150–290%) but remarkably increased 5-HT levels (540–900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

Association between gene variants and response to buprenorphine maintenance treatment

A variety of studies were addressed to differentiate responders and non-responders to substitution treatment among heroin dependent patients, without conclusive findings. In particular, preliminary pharmacogenetic findings have been reported to predict treatment effectiveness in mental health and substance use disorders. Aim of the present study was to investigate the possible association of buprenorphine (BUP) treatment outcome with gene variants that may affect kappa-opioid receptors and dopamine system function. One hundred and seven heroin addicts (West European, Caucasians) who underwent buprenorphine maintenance treatment were genotyped and classified into two groups (A and B) on the basis of treatment outcome. Non-responders to buprenorphine (group B) have been identified taking into account early drop out, continuous use of heroin, severe behavioral or psychiatric problems, misbehavior and diversion during the 6 months treatment period. No difference was evidenced between responders and non-responders to BUP in the frequency of kappa opioid receptor (OPRK1) 36G>T SNP. The frequency of dopamine transporter (DAT) gene polymorphism (SLC6A3/DAT1), allele 10, was evidently much higher in “non-responder” than in “responder” individuals (64.9% vs. 55.93%) whereas the frequency of the category of other alleles (6, 7 and 11) was higher in responder than in non-responder individuals (11.02% vs. 2.13% respectively). On one hand, the hypothesis that possible gene-related changes in kappa-opioid receptor could consistently affect buprenorphine pharmacological action and clinical effectiveness was not confirmed in our study, at least in relation to the single nucleotide polymorphism 36G>T. On the other hand, the possibility that gene-related dopamine changes could have reduced BUP effectiveness and impaired maintenance treatment outcome was cautiously supported by our findings. DAT1 gene variants such as allele 10, previously reported in association with personality and behavioral problems, would have influenced the effects of BUP-induced dopamine release, modulated through mu and kappa opioid receptors, and probably the related reinforcing capacity of the drug.