Drug-evoked adaptations in the mesolimbic dopamine system are postulated to drive opioid abuse and addiction. These adaptations vary in magnitude and direction following different patterns of opioid exposure, but few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. We exposed male and female mice to morphine for one week, with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with either naloxone-precipitated or spontaneous withdrawal. Continuous morphine exposure caused tolerance to the psychomotor-activating effects of morphine, whereas both intermittent and interrupted morphine exposure caused long-lasting psychomotor sensitization. Given links between locomotor sensitization and mesolimbic dopamine signaling, we used fiber photometry and a genetically encoded dopamine sensor to conduct longitudinal measurements of dopamine dynamics in the nucleus accumbens. Locomotor sensitization caused by interrupted morphine exposure was accompanied by enhanced dopamine signaling in the nucleus accumbens. To further assess downstream consequences on striatal gene expression, we used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in both nucleus accumbens and dorsal striatum, dramatically increasing differential gene expression and engaging unique signaling pathways. Our study indicates that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may, therefore, represent a strategy to minimize iatrogenic effects on brain reward circuits.

Adenosine A receptors are putative therapeutic targets for neurological disorders. The adenosine A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.

Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type–specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.

The l-opioid receptor regulates reward derived from both drug use and natural experiences, including social interaction, through actions in the nucleus accumbens. Here, we studied nucleus accumbens microcircuitry and social behavior in male and female mice with heterozygous genetic knockout of the l-opioid receptor (Oprm1 1/2 ). This genetic condition models the partial reduction of l-opioid receptor signaling reported in several neuropsychiatric disorders. We first analyzed inhibitory synapses in the nucleus accumbens, using methods that differentiate between medium spiny neurons (MSNs) expressing the D1 or D2 dopamine receptor. Inhibitory synaptic transmission was increased in D2-MSNs of male mutants, but not female mutants, while the expression of gephyrin mRNA and the density of inhibitory synaptic puncta at the cell body of D2-MSNs was increased in mutants of both sexes. Some of these changes were more robust in Oprm1 1/2 mutants than Oprm1 2/2 mutants, demonstrating that partial reductions of l-opioid signaling can have large effects. At the behavioral level, social conditioned place preference and reciprocal social interaction were diminished in Oprm1 1/2 and Oprm1 2/2 mutants of both sexes. Interaction with Oprm1 mutants also altered the social behavior of wild-type test partners. We corroborated this latter result using a social preference task, in which wild-type mice preferred interactions with another typical mouse over Oprm1 mutants. Surprisingly, Oprm1 2/2 mice preferred interactions with other Oprm1 2/2 mutants, although these interactions did not produce a conditioned place preference. Our results support a role for partial dysregulation of l-opioid signaling in social deficits associated with neuropsychiatric conditions. Significance StatementActivation of the m-opioid receptor plays a key role in the expression of normal social behaviors. In this study, we examined brain function and social behavior of female and male mice, with either partial or complete genetic deletion of m-opioid receptor expression. We observed abnormal social behavior following both genetic manipulations, as well as changes in the structure and function of synaptic input to a specific population of neurons in the nucleus accumbens, which is an important brain region for social behavior. Synaptic changes were most robust when m-opioid receptor expression was only partially lost, indicating that small reductions in m-opioid receptor signaling can have a large impact on brain function and behavior.

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