Explore the vast range of titles available.

RationaleMethamphetamine (MA) addiction is a major public health issue in the USA, with a poorly understood genetic component. We previously identified heterogeneous nuclear ribonucleoprotein H1 (Hnrnph1; H1) as a quantitative trait gene underlying sensitivity to MA-induced behavioral sensitivity. Mice heterozygous for a frameshift deletion in the first coding exon of H1 (H1+/−) showed reduced MA phenotypes including oral self-administration, locomotor activity, dopamine release, and dose-dependent differences in MA conditioned place preference. However, the effects of H1+/− on innate and MA-modulated reward sensitivity are not known.ObjectivesWe examined innate reward sensitivity and facilitation by MA in H1+/− mice via intracranial self-stimulation (ICSS).MethodsWe used intracranial self-stimulation (ICSS) of the medial forebrain bundle to assess shifts in reward sensitivity following acute, ascending doses of MA (0.5–4.0 mg/kg, i.p.) using a within-subjects design. We also assessed video-recorded behaviors during ICSS testing sessions.ResultsH1+/− mice displayed reduced normalized maximum response rates in response to MA. H1+/− females had lower normalized M50 values compared to wild-type females, suggesting enhanced reward facilitation by MA. Finally, regardless of genotype, there was a dose-dependent reduction in distance to the response wheel following MA administration, providing an additional measure of MA-induced reward-driven behavior.ConclusionsH1+/− mice displayed a complex ICSS phenotype following MA, displaying indications of both blunted reward magnitude (lower normalized maximum response rates) and enhanced reward sensitivity specific to H1+/− females (lower normalized M50 values).

Drug addiction is characterized by relapse when addicts are re-exposed to drug-associated environmental cues, but the neural mechanisms underlying cue-induced relapse are unclear. In the present study we investigated the role of a specific dopaminergic (DA) pathway from ventral tegmental area (VTA) to nucleus accumbens core (NAcore) in mouse cue-induced relapse. Optical intracranial self-stimulation (oICSS) was established in DAT-Cre transgenic mice. We showed that optogenetic excitation of DA neurons in the VTA or their projection terminals in NAcore, NAshell or infralimbic prefrontal cortex (PFC-IL) was rewarding. Furthermore, activation of the VTA-NAcore pathway alone was sufficient and necessary to induce reinstatement of oICSS. In cocaine self-administration model, cocaine-associated cues activated VTA DA neurons as assessed by intracellular GCaMP signals. Cue-induced reinstatement of cocaine-seeking was triggered by optogenetic stimulation of the VTA-NAcore pathway, and inhibited by chemogenetic inhibition of this pathway. Together, these results demonstrate that cue-induced reinstatement of reward seeking is in part mediated by activation of the VTA-NAcore DA pathway.

The reward circuitry of the brain consists of neurons that synaptically connect a wide variety of nuclei. Of these brain regions, the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play central roles in the processing of rewarding environmental stimuli and in drug addiction. The psychoactive properties of marijuana are mediated by the active constituent, Δ9‐THC, interacting primarily with CB1 cannabinoid receptors in a large number of brain areas. However, it is the activation of these receptors located within the central brain reward circuits that is thought to play an important role in sustaining the self‐administration of marijuana in humans, and in mediating the anxiolytic and pleasurable effects of the drug. Here we describe the cellular circuitry of the VTA and the NAc, define the sites within these areas at which cannabinoids alter synaptic processes, and discuss the relevance of these actions to the regulation of reinforcement and reward. In addition, we compare the effects of Δ9‐THC with those of other commonly abused drugs on these reward circuits, and we discuss the roles that endogenous cannabinoids may play within these brain pathways, and their possible involvement in regulating ongoing brain function, independently of marijuana consumption. We conclude that, whereas Δ9‐THC alters the activity of these central reward pathways in a manner that is consistent with other abused drugs, the cellular mechanism through which this occurs is likely different, relying upon the combined regulation of several afferent pathways to the VTA. British Journal of Pharmacology (2004) 143, 227–234. doi:10.1038/sj.bjp.0705931

Chronic pain is a persistent and debilitating health problem. Although the use of analgesics such as opioids is useful in mitigating pain, their prolonged use is associated with unwanted effects including abuse liability. This study assesses the antinociceptive effect of combining subtherapeutic doses of two opioids (morphine or tramadol) with the synthetic cannabinoid CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan -2-yl)phenol). It also evaluates the associated adverse effects of these drugs and combinations. Adult male rats were injected with intraplantar complete Freund’s adjuvant (CFA) to produce mechanical allodyia. Antinociceptive effect of morphine, tramadol, the synthetic cannabinoid CP55940, or their combinations was evaluated three to nine days post-CFA injections. Intracranial self-stimulation (ICSS) was utilized to evaluate the abuse liability of these drugs or their combinations. All drugs alone produced a dose-dependent antinociceptive effect. Morphine produced minimal effect on ICSS, but both tramadol and CP55940 produced dose-dependent depression of ICSS. Morphine at a dose of 0.32 mg/kg enhanced the antinociceptive effects of CP55940, in that, CP55940 produced antinociception at a lower dose (0.1 mg/kg) when compared to the vehicle. The aforementioned combinations did not change CP55940-induced depression of ICSS. On the other hand, tramadol failed to enhance the antinociceptive effect of CP55940. Our data suggest that combining CP55940 with morphine, but not tramadol, shows a better antinociceptive profile with no additional risk of abuse liability, which represents a potential pain management approach.

The reward-mountain model relates the vigor of reward seeking to the strength and cost of reward. Application of this model provides information about the stage of processing at which manipulations such as drug administration, lesions, deprivation states, and optogenetic interventions act to alter reward seeking. The model has been updated by incorporation of new information about frequency following in the directly stimulated neurons responsible for brain stimulation reward and about the function that maps objective opportunity costs into subjective ones. The behavioral methods for applying the model have been updated and improved as well. To assess the impact of these changes, two related predictions of the model that were supported by earlier work have been retested: (1) altering the duration of rewarding brain stimulation should change the pulse frequency required to produce a reward of half-maximal intensity, and (2) this manipulation should not change the opportunity cost at which half-maximal performance is directed at earning a maximally intense reward. Prediction 1 was supported in all six subjects, but prediction 2 was supported in only three. The latter finding is interpreted to reflect recruitment, at some stimulation sites, of a heterogeneous reward substrate comprising dual, parallel circuits that integrate the stimulation-induced neural signals.

A markedly reduced interest or pleasure in activities previously considered pleasurable is a main symptom in mood disorder and psychosis and is often present in other psychiatric disorders and neurodegenerative diseases. This condition can be labeled as \"anhedonia,\" although in its most rigorous connotation the term refers to the lost capacity to feel pleasure that is one aspect of the complex phenomenon of processing and responding to reward. The responses to rewarding stimuli are relatively easy to study in rodents, and the experimental conditions that consistently and persistently impair these responses are used to model anhedonia. To this end, long-term exposure to environmental aversive conditions is primarily used, and the resulting deficits in reward responses are often accompanied by other deficits that are mainly reminiscent of clinical depressive symptoms. The different components of impaired reward responses induced by environmental aversive events can be assessed by different tests or protocols that require different degrees of time allocation, technical resources, and equipment. Rodent models of anhedonia are valuable tools in the study of the neurobiological mechanisms underpinning impaired behavioral responses and in the screening and characterization of drugs that may reverse these behavioral deficits. In particular, the antianhedonic or promotivational effects are relevant features in the spectrum of activities of drugs used in mood disorders or psychosis. Thus, more than the model, it is the choice of tests that is crucial since it influences which facets of anhedonia will be detected and should be tuned to the purpose of the study.

Aim Attention‐deficit/hyperactivity disorder is a heterogeneous neurobiological disorder that is characterized by inattention, impulsivity, and an increase in motor activity. Although methylphenidate has been used as a medication for decades, unknown is whether methylphenidate treatment can cause drug dependence in patients with attention‐deficit/hyperactivity disorder. This study investigated the reward‐enhancing effects of methylphenidate using intracranial self‐stimulation in an animal model of attention‐deficit/hyperactivity disorder, dopamine transporter knockout mice. Methods For the intracranial self‐stimulation procedures, the mice were trained to nosepoke to receive direct electrical stimulation via an electrode that was implanted in the lateral hypothalamus. After the acquisition of nosepoke responding for intracranial self‐stimulation, the effects of methylphenidate on intracranial self‐stimulation were investigated. Results In the progressive‐ratio procedure, dopamine transporter knockout mice exhibited an increase in intracranial self‐stimulation compared with wild‐type mice. Treatment with 5 and 10 mg/kg methylphenidate increased intracranial self‐stimulation responding in wild‐type mice. Methylphenidate at the same doses did not affect intracranial self‐stimulation responding in dopamine transporter knockout mice. We then investigated the effects of high‐dose methylphenidate (60 mg/kg) in a rate‐frequency procedure. High‐dose methylphenidate significantly decreased intracranial self‐stimulation responding in both wild‐type and dopamine transporter knockout mice. Conclusions These results suggest that low‐dose methylphenidate alters the reward system (ie, increases intracranial self‐stimulation responding) in wild‐type mice via dopamine transporter inhibition, whereas dopamine transporter knockout mice do not exhibit such alterations. High‐dose methylphenidate appears to suppress intracranial self‐stimulation responding not through dopamine transporter inhibition but rather through other mechanisms. These results support the possibility that methylphenidate treatment for attention‐deficit/hyperactivity disorder does not increase the risk of drug dependence, in attention‐deficit/hyperactivity disorder patients with dopamine transporter dysfunction. This study investigated the reward‐enhancing effects of methylphenidate (MPH) using intracranial self‐stimulation (ICSS) in an animal model of ADHD, dopamine transporter knockout (DAT‐KO) mice. Low‐dose MPH affects the reward system (ie, increased ICSS responding) in wild‐type mice via DAT inhibition, but not in DAT‐KO mice. MPH treatment for ADHD may not increase the risk of drug dependence, in ADHD patients with DAT dysfunction.