TL;DR
Overall, the existing findings support TAAR1 as a therapeutic target for treatment of substance use disorders, however, translating these findings into effective human pharmacotherapies requires navigating ligand-specific effects and pharmacokinetic demands and defining the role of human TAAR1 genetic diversity in therapeutic response.
This narrative review provides evidence regarding the impact of trace amine-associated receptor 1 (TAAR1) agonists on rodent models of substance use disorders (SUDs). We delineated the fundamental aspects of the pharmacodynamics and pharmacokinetics of TAAR1 agonists and collected in vivo studies that investigated TAAR1 activation in behavioral sensitization, conditioned behaviors, or self-administration models. TAAR1 agonists have demonstrated efficacy in suppressing addiction-relevant behaviors associated with cocaine. Their effectiveness is largely consistent across intrinsic activity levels, routes of administration, and experimental protocols. TAAR1 agonists also show certain preliminary promise as amphetamine psychostimulants, nicotine, alcohol, and opioids, but the number of studies remains very small. The reported effects occurred at doses that did not impair natural reward behavior. Moreover, the findings for alcohol use disorder demonstrated efficacy in both male and female subjects. Conversely, opioid studies have presented mixed results, highlighting the need for further investigation. There is a lack of studies examining the effects of TAAR1 agonists in female subjects, which is crucial for understanding potential sex differences in treatment responses. The limited number of research groups working on this topic raises concerns regarding bias and reproducibility. Future research should address these gaps, expand investigations to diverse populations, and replicate findings across laboratories to strengthen evidence for TAAR1 agonists as potential therapeutic agents for cocaine-use disorder.
While combined antiretroviral therapy (cART) has transitioned HIV-1 into a manageable chronic condition, it fails to eradicate latent viral reservoirs in the central nervous system (CNS) that drive persistent neuroinflammation and synaptodendritic injury. Consequently, people living with human immunodeficiency virus type-1 (HIV-1) often utilize cannabis to manage neurological symptoms, yet the long-term impact of exogenous cannabinoids on the HIV-1-burdened brain remains poorly understood. In this study, we utilized the HIV-1 Tg26 mouse model to evaluate how chronic Δ9-tetrahydrocannabinol (THC, 3mg/kg) exposure influences motor coordination, thermal nociception, and endocannabinoid (eCB) signaling in the context of constitutive viral protein expression. Our results demonstrate that HIV-1 viral protein expression was associated with impaired acquisition of cerebellum-dependent motor learning in a sex-dependent manner. This deficit was primarily driven by females and coincided with altered markers of eCB plasticity, characterized by elevated monoacylglycerol lipase (MAGL) expression and a depletion of 2-arachidonoylglycerol (2-AG). Conversely, males exhibit increased cerebellar CB1R and CB2R expression, which paralleled preserved rotarod performance. In the spinal cord, viral protein expression was associated with thermal hyposensitivity and a reduction in 2-AG and cannabinoid receptor levels, a pattern consistent with HIV-1-associated alterations in sensory processing circuits. While chronic THC failed to produce detectable antinociceptive effects, consistent with spinal CB1R downregulation, it successfully attenuated the temporal decline of motor coordination with upregulating cerebellar CB1R. Data from a separate acute THC cohort demonstrated detectable THC and metabolite concentrations in plasma and cortex, while also revealing sex- and genotype-dependent differences in these measures. Together, these findings identify sex-specific eCB signaling as a critical factor associated with the neurobiological response to HIV-1 proteins and provide a biological framework for understanding sex-dependent variability in cannabinoid efficacy.
Background Inflammation-associated depression is a subtype of major depressive disorder that is often resistant to conventional pharmacotherapies, which act in a regionally non-specific manner and therefore also produce unwanted side effects. Here we test GPR151, an orphan GPCR associated with inflammation and highly expressed in the habenula—a region linked to negative valence and depression—as a therapeutic target for inflammation-associated depression. Methods We integrated mouse and human habenular expression analyses with genetic loss-of-function and adult habenular re-expression approaches in mice. Gpr151 knockout mice and littermate controls were exposed to lipopolysaccharide (LPS) inflammatory challenge and assessed for stress coping and motivated behavior, body weight loss, and peripheral immune activation. To test whether adult habenular GPR151 expression is sufficient to restore inflammation-associated behavioral vulnerability, GPR151 was re-expressed in the habenula of knockout mice. Results GPR151 was exceptionally enriched in the habenula and showed conserved topographic organization and similar expression relationships with habenular marker genes in mice and humans. Following LPS challenge, male Gpr151 knockout mice showed reduced passive coping despite body weight loss and immune activation comparable to littermate controls. Adult habenular GPR151 re-expression increased LPS-induced amotivation in male knockout mice without increasing LPS-induced weight loss or immune activation. Female Gpr151 knockout mice also showed reduced passive coping after LPS challenge; however, habenular GPR151 re-expression was insufficient to increase LPS-induced amotivation in females. Conclusions These findings identify GPR151 as a conserved, regionally enriched regulator of behavioral sensitivity to inflammatory challenge and support GPR151 as a candidate therapeutic target for inflammation-associated depression.