Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) represent a technical revolution in integrative neuroscience. However, the first used ligands exhibited dose-dependent selectivity for their molecular target, leading to potential unspecific effects. Compound 21 (C21) was recently proposed as an alternative, but in vivo characterization of its properties is not sufficient yet. Here, we evaluated its potency to selectively modulate the activity of nigral dopaminergic (DA) neurons through the canonical DREADD receptor hM4Di using TH-Cre rats. In males, 1 mg.kg-1 of C21 strongly increased nigral neurons activity in control animals, indicative of a significant off-target effect. Reducing the dose to 0.5 mg.kg-1 circumvented this unspecific effect, while activated the inhibitory DREADDs and selectively reduced nigral neurons firing. In females, 0.5 mg.kg-1 of C21 induced a transient and residual off-target effect that may mitigated the inhibitory DREADDs-mediated effect. This study raises up the necessity to test selectivity and efficacy of chosen ligands for each new experimental condition.

Apathy and Impulse Control Disorders: Yin & Yang of Dopamine Dependent Behaviors.

Neuropsychiatric symptoms are common non-motor symptoms in Parkinson's disease (PD). Apathy and impulse control disorders (ICD) are two opposite motivational expressions of a continuous behavioural spectrum involving hypo- and hyperdopaminergia. Both syndromes share pathological (decreased vs increased) dopamine receptor stimulation states. Apathy belongs to the spectrum of hypodopaminergic symptoms together with anhedonia, anxiety and depression. Apathy is a key symptom of PD which worsens with disease progression. Animal models, imaging and pharmacological studies concur in pointing out dopaminergic denervation in the aetiology of parkinsonian apathy with a cardinal role of decreased tonic D2/D3 receptor stimulation. ICDs are part of the hyperdopaminergic behavioural spectrum, which also includes punding, and dopamine dysregulation syndrome (DDS), which are all related to non-physiological dopaminergic stimulation induced by antiparkinsonian drugs. According to clinical data tonic D2/D3 receptor stimulation can be sufficient to induce ICDs. Clinical observations in drug addiction and PD as well as data from studies in dopamine depleted rodents provide hints allowing to argue that both pulsatile D1 and D2 receptor stimulation and the severity of dopaminergic denervation are risk factors to develop punding behavior and DDS. Imaging studies have shown that the brain structures involved in drug addiction are also involved in hyperdopaminergic behaviours with increase of bottom-up appetitive drive and decrease in prefrontal top down behavioural control.

Fos immunolabelling evidence for brain regions involved in the Pavlovian degraded contingency effect and in its disruption by atropine.

Using a fear conditioning preparation, [Carnicella, S., Pain, L., Oberling, P., 2005a. Cholinergic effects on fear conditioning I: The degraded contingency effect is disrupted by atropine but reinstated by physostigmine. Psychopharmacology 178, 524-532] showed that the muscarinic receptor antagonist atropine disrupted the degraded contingency effect (DCE) in the rat, that is, the processes by which contextual memory competes with cued memory for the control over conditioned responding. Here, we investigated neural substrates involved in the expression of normal and atropine-disrupted DCE, using the protein Fos as a marker of neuronal activity. Compared to contingent conditioning, the DCE was associated with a decrease of the amount of Fos immunoreactive neurons within the auditory system and the amygdala and an increase within the medial prefrontal cortex (mPFC). Compared to the normal DCE, atropine-induced disruption of the DCE was associated with an increase of the amount of Fos immunoreactive neurons within the central nucleus of the amygdala. When atropine-induced suppression of the DCE, Fos pattern was modified in the mPFC with a change in Fos immunoreactivity, but no longer associated with the DCE. However, the mPFC was the unique structure studied in which the amount of Fos immunoreactive neurons was differentially affected according to both the conditioning procedure and the pharmacological treatment. These results are discussed in the framework of the cholinergic modulation of context processing in the rat and are put in parallel with an emerging set of studies in humans regarding the role of the PFC in such processing.