The cannabinoid CB agonist LY2828360 suppresses neuropathic pain behavior and attenuates morphine tolerance and conditioned place preference in rats.

Cannabinoid CB agonists show promise as analgesics because they lack unwanted side effects associated with direct activation of CB receptors. CB receptor activation suppresses pathological pain in animal models, but the types of pain that best respond to CB agonists are incompletely understood. This gap in knowledge may contribute to failures in clinical translation.

Negative allosteric modulation of CB1 cannabinoid receptor signalling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators.

Negative allosteric modulation of CB1 cannabinoid receptor signaling decreases intravenous morphine self-administration and relapse in mice.

The endocannabinoid system interacts with the reward system to modulate responsiveness to natural reinforcers, as well as drugs of abuse. Previous preclinical studies suggested that direct blockade of CB1 cannabinoid receptors (CB1R) could be leveraged as a potential pharmacological approach to treat substance use disorder, but this strategy failed during clinical trials due to severe psychiatric side effects. Alternative strategies have emerged to circumvent the side effects of direct CB1 binding through the development of allosteric modulators.

Inhibition of PSD95-nNOS protein-protein interactions decreases morphine reward and relapse vulnerability in rats.

Glutamate signalling through the N-methyl-d-aspartate receptor (NMDAR) activates the enzyme neuronal nitric oxide synthase (nNOS) to produce the signalling molecule nitric oxide (NO). We hypothesized that disruption of the protein-protein interaction between nNOS and the scaffolding protein postsynaptic density 95 kDa (PSD95) would block NMDAR-dependent NO signalling and represent a viable therapeutic route to decrease opioid reward and relapse-like behaviour without the unwanted side effects of NMDAR antagonists. We used a conditioned place preference (CPP) paradigm to evaluate the impact of two small-molecule PSD95-nNOS inhibitors, IC87201 and ZL006, on the rewarding effects of morphine.

Peripheral nerve injury promotes morphine-seeking behavior in rats during extinction.

Chronic neuropathic pain and prescription opioid abuse represent highly interconnected societal problems. We used a rat model of spared nerve injury (SNI) and an intravenous drug self-administration paradigm to investigate the impact of a neuropathic pain state on morphine-seeking behavior in extinction (i.e.

Cocaine experience abolishes the motivation suppressing effect of CRF in the ventral midbrain.

Stress affects dopamine-dependent behaviors in part through the actions of corticotropin releasing factor (CRF) in the ventral tegmental area (VTA). For example, acute stress engages CRF signaling in the VTA to suppress the motivation to work for food rewards. In contrast, acute stress promotes drug-seeking behavior through the actions of CRF in the VTA.

Operant Costs Modulate Dopamine Release to Self-Administered Cocaine.

The costs associated with obtaining illicit drugs can fluctuate depending upon the relative drug availability. As a consequence of the changing costs, the effort that one must exert to obtain drugs is dynamic. Considerable evidence illustrates a critical role for dopamine in the ventral medial striatum in mediating drug reinforcement.

Ventral Tegmental Area Afferents and Drug-Dependent Behaviors.

Drug-related behaviors in both humans and rodents are commonly thought to arise from aberrant learning processes. Preclinical studies demonstrate that the acquisition and expression of many drug-dependent behaviors involves the ventral tegmental area (VTA), a midbrain structure comprised of dopamine, GABA, and glutamate neurons. Drug experience alters the excitatory and inhibitory synaptic input onto VTA dopamine neurons, suggesting a critical role for VTA afferents in mediating the effects of drugs.

Dopamine release regulation by astrocytes during cerebral ischemia.

Brain ischemia triggers excessive release of neurotransmitters that mediate neuronal damage following ischemic injury. The striatum is one of the areas most sensitive to ischemia. Release of dopamine (DA) from ischemic neurons is neurotoxic and directly contributes to the cell death in affected areas.

L-DOPA-induced increase in TH-immunoreactive striatal neurons in parkinsonian mice: insights into regulation and function.

Tyrosine hydroxylase (TH)-immunoreactive (ir) neurons have been found in the striatum after dopamine depletion; however, little is known about the mechanism underlying their appearance or their functional significance. We previously showed an increase in striatal TH-ir neurons after L-DOPA treatment in mice with unilateral 6-OHDA lesions in the striatum. In the present study, we further examined the time-course and persistence of the effects of chronic L-DOPA treatment on the appearance and regulation of TH-ir neurons as well as their possible function.

Nrf2 deficiency potentiates methamphetamine-induced dopaminergic axonal damage and gliosis in the striatum.

Oxidative stress that correlates with damage to nigrostriatal dopaminergic neurons and reactive gliosis in the basal ganglia is a hallmark of methamphetamine (METH) toxicity. In this study, we analyzed the protective role of the transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2), a master regulator of redox homeostasis, in METH-induced neurotoxicity. We found that Nrf2 deficiency exacerbated METH-induced damage to dopamine neurons, shown by an increase in loss of tyrosine hydroxylase (TH)- and dopamine transporter (DAT)-containing fibers in striatum.

Dopamine D2-receptor knockout mice are protected against dopaminergic neurotoxicity induced by methamphetamine or MDMA.

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA), amphetamine derivatives widely used as recreational drugs, induce similar neurotoxic effects in mice, including a marked loss of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum. Although the role of dopamine in these neurotoxic effects is well established and pharmacological studies suggest involvement of a dopamine D2-like receptor, the specific dopamine receptor subtype involved has not been determined. In this study, we used dopamine D2 receptor knock-out mice (D2R(-/-)) to determine whether D2R is involved in METH- and MDMA-induced hyperthermia and neurotoxicity.