Neurokinin-1 (NK1) receptor antagonists as possible therapeutics for psychostimulant use disorders.

Abuse of and addiction to psychostimulants such as cocaine or amphetamines remain a significant societal burden, and attempts at successfully developing effective treatments for substance use disorders involving psychostimulants have been disappointingly unsuccessful to date. In addition, most pharmacologically based approaches to treating psychostimulant use disorders have largely focused on targeting monoaminergic or amino acid neurotransmission, with little emphasis being placed on neuropeptide systems. One such neuropeptide system that has received little attention is the tachykinin family of peptides and their corresponding neurokinin (NK) receptor subtypes designated NK1, NK2, and NK3. Tachykinins and their receptors are widely expressed in numerous cell types in the periphery and central nervous system, and in the latter, regulate fundamental processes such as nociception, reward, motivation, affect, and stress responses. In recent years, various small molecule brain penetrant NK1 antagonists have been developed which appear to be beneficial and well tolerated in patients undergoing treatment for chemotherapy-induced and post-operative nausea and vomiting. The purpose of this review is to summarize the small body of preclinical and clinical studies that suggest NK1 antagonists may be of potential use in the treatment of substance use disorders involving psychostimulants. Additional topics of discussion will be the importance of full receptor occupancy and known species differences in NK1 receptor ligand binding, which represent significant obstacles to utilizing standard rodent models of psychostimulant addiction for future screening of potentially efficacious NK1 antagonists.

mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex.

Positive and negative allosteric modulators (PAMs and NAMs, respectively) of type 5 metabotropic glutamate receptors (mGluR5) are currently being investigated as novel treatments for neuropsychiatric diseases including drug addiction, schizophrenia, and Fragile X syndrome. However, only a handful of studies have examined the effects of mGluR5 PAMs or NAMs on the structural plasticity of dendritic spines in otherwise naïve animals, particularly in brain regions mediating executive function. In the present study, we assessed dendritic spine density and morphology in pyramidal cells of the medial prefrontal cortex (mPFC) after repeated administration of either the prototypical mGluR5 PAM 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5- yl)benzamide (CDPPB, 20 mg/kg), the clinically utilized mGluR5 NAM 1-(3-chlorophenyl)-3-(3-methyl-5-oxo-4Himidazol- 2-yl)urea (fenobam, 20 mg/kg), or vehicle in male Sprague-Dawley rats. Following once daily treatment for 10 consecutive days, coronal brain sections containing the mPFC underwent diolistic labeling and 3D image analysis of dendritic spines. Compared to vehicle treated animals, rats administered fenobam exhibited significant increases in dendritic spine density and the overall frequency of spines with small (<0.2 µm) head diameters, decreases in frequency of spines with medium (0.2-0.4 µm) head diameters, and had no changes in frequency of spines with large head diameters (>0.4 µm). Administration of CDPPB had no discernable effects on dendritic spine density or morphology, and neither CDPPB nor fenobam had any effect on spine length or volume. We conclude that mGluR5 PAMs and NAMs differentially affect mPFC dendritic spine structural plasticity in otherwise naïve animals, and additional studies assessing their effects in combination with cognitive or behavioral tasks are needed.