Biology subjects

D'Ottavio, G.

Publications and source records attributed to D'Ottavio, G..

3 recordsLinked to original sources

bioRxiv2026

Neurometabolic signatures of addiction vulnerability and heroin versus social seeking: a PET study in rats

Only a subset of heroin users develop addiction, characterized by binge-like heroin use and preference for heroin over other rewards, including social rewards. We recently established a rat model of these features. We trained rats to lever-press for social interaction and heroin (or saline, control) infusions and then tested heroin- and social-seeking and heroin-vs.-social choice. During 3-5 abstinence weeks, we used 2-deoxy-2-[{superscript 1}F]fluoro-D-glucose (FDG) PET imaging to assess regional brain metabolic activity at rest (homecage) and during heroin and social seeking. We assessed regional differences in FDG uptake using unbiased voxel-wise analysis and statistical parametric mapping, and correlated FDG uptake with principle-component-analysis-derived addiction severity score incorporating heroin intake, binge-like episodes, and heroin preference. Compared with saline-trained rats, heroin-trained rats showed overall higher FDG uptake across multiple brain regions at rest and during both reward-seeking tests. Comparison of heroin-vs.-social-seeking in heroin-trained rats showed higher uptake in claustrum/lateral striatum and auditory cortex during social seeking. Analysis of individual differences showed that addiction severity was primarily associated with metabolic alterations under resting conditions rather than during heroin- or social-seeking. At rest, higher addiction severity was associated with lower uptake in piriform cortex and higher uptake in ventral hippocampus, whereas during heroin-seeking, addiction severity was associated with lower uptake in post-subiculum and cerebellum. Addiction severity was not associated with differences in social seeking or FDG uptake during social seeking. These findings identify neurometabolic features of social and heroin seeking and heroin addiction vulnerability that can potentially serve as brain biomarkers and targets for neuromodulation. Significance StatementHeroin addiction develops in only a subset of users, yet the determinants of vulnerability versus resilience to addiction remain largely unknown. We combined a rat model capturing key features of heroin addiction, including binge-like heroin intake and preference for heroin over social interaction, with behavioral heroin- and social-seeking assays and longitudinal whole-brain metabolic imaging using FDG-PET. We identified distinct patterns of neurometabolic alterations associated with heroin self-administration and addiction severity at rest and in the context of heroin seeking. In contrast, heroin self-administration and addiction severity were not significantly associated with neurometabolic alterations during social seeking. These findings highlight brain-wide neurometabolic features of vulnerability to heroin addiction that can serve as brain biomarkers and targets for neuromodulation.

neuroscience↗

bioRxiv2025

Sex-dimorphic effects of neuromelanin buildup in rodent nigral dopamine neurons: implications for sex-biased vulnerability in Parkinson's disease

Neuromelanin (NM) is a dark pigment accumulating with age in human substantia nigra pars compacta (SNpc) dopamine (DA) neurons, conferring the dark look that inspired nigral areas name. Despite NM has long been associated with Parkinsons disease (PD), as melanized neurons favorably degenerate during disease development, NM functions within SNpc DA neurons are still mostly elusive. Here, by exploiting an NM-producing rat model generated by viral vector-induced expression of human Tyrosinase (hTyr), we inspected NM impact on nigral DA neurons survival and activity, on mitochondrial functionality of SNpc, and behaviors resembling non-motor and motor PD symptoms. Our data reveal sex dimorphism in NM effects on nigrostriatal dopamine circuit, with sex-biased alterations in neuronal firing activity and underlying intrinsic currents, nigral mitochondrial functions, and non-motor PD symptoms (anxiety). In conclusion, this study discloses unrealized NM effects within nigral DA neurons, advancing our comprehension of sex-specific features shaping sex-biased vulnerability to PD.

neuroscience↗

bioRxiv2024

Translating human drug use patterns into rat models: exploring spontaneous interindividual differences via refined drug self-administration procedures

Heroin and cocaine users tailor their dosage and frequency of use, as well as their method of administration, to maximize the drugs pleasurable effects and prevent withdrawal symptoms. On the other hand, many preclinical self-administration and choice experiments employ fixed unit doses and mandatory timeouts after doses (known as discrete dimension procedures). These restrictions fail to consider the distinct pharmacokinetic properties of heroin and cocaine, leading to uniform and comparable behaviors (including drug-taking patterns). This uniformity contrasts sharply with the significantly different ways humans use heroin and cocaine, which are characterized by highly individualized drug use behaviors. Here, we introduce a no-timeout procedure that overcomes this limitation (continuous dimension procedure). We analyzed the heroin and cocaine taking- and seeking-patterns and estimated drug-brain levels in the presence or absence of timeout between drug injections. We further assessed how absence of timeout and the availability of drug or social peer (access time to the two rewards) affect drug preference. Removing the timeout had a profound effect on pattern of heroin taking and seeking, promoting the emergence of burst-like drug intake and social withdrawal as revealed by a discrete choice procedure. On the other hand, timeout removal had a lesser impact on cocaine taking and seeking and did not impact social preference. By removing timeout during self-administration and increasing the access time during choice resulted in a self-administration procedure that more closely mimic human heroin intake, offering a platform to identify novel medications.

neuroscience↗