Complex 33-beam simulated galactic cosmic radiation exposure impacts cognitive function and prefrontal cortex neurotransmitter networks in male mice.

Astronauts will encounter extended exposure to galactic cosmic radiation (GCR) during deep space exploration, which could impair brain function. Here, we report that in male mice, acute or chronic GCR exposure did not modify reward sensitivity but did adversely affect attentional processes and increased reaction times. Potassium (K+)-stimulation in the prefrontal cortex (PFC) elevated dopamine (DA) but abolished temporal DA responsiveness after acute and chronic GCR exposure. Unlike acute GCR, chronic GCR increased levels of all other neurotransmitters, with differences evident between groups after higher K+-stimulation. Correlational and machine learning analysis showed that acute and chronic GCR exposure differentially reorganized the connection strength and causation of DA and other PFC neurotransmitter networks compared to controls which may explain space radiation-induced neurocognitive deficits.

Nicotine modifies cocaine responding in a concurrent self-administration model.

BACKGROUND: Preclinical models of cocaine use disorder (CUD) have not yielded any FDA-approved pharmacotherapies, potentially due to a focus on cocaine use in isolation, which may not fully translate to real-world drug taking patterns. Cocaine and nicotine are commonly used together, and clinical research suggests that nicotine may increase the potency and reinforcing strength of cocaine. In this study, we sought to determine whether and how the addition of nicotine would alter ongoing intravenous cocaine self-administration and motivation to take cocaine in rats. METHODS: Male Sprague-Dawley rats self-administered cocaine alone on a long access, Fixed Ratio one (FR1) schedule, and then switched to a combination of cocaine and nicotine. Finally, rats responded on a Progressive Ratio (PR) schedule for several doses of cocaine alone and in combination with a single dose of nicotine. RESULTS: Under long access conditions, rats co-self-administering cocaine and nicotine responded less and with decreased response rates than for cocaine alone and did not escalate responding. However, under PR conditions that test motivation to take drugs, the dose response curve for the combination was shifted upwards relative to cocaine alone. CONCLUSIONS: Together, these results suggest that nicotine may enhance the reinforcing strength of cocaine, increasing PR responding for cocaine across the dose response curve.

GDNF gene therapy for alcohol use disorder in male non-human primates.

Alcohol use disorder (AUD) exacts enormous personal, social and economic costs globally. Return to alcohol use in treatment-seeking patients with AUD is common, engendered by a cycle of repeated abstinence-relapse episodes even with use of currently available pharmacotherapies. Repeated ethanol use induces dopaminergic signaling neuroadaptations in ventral tegmental area (VTA) neurons of the mesolimbic reward pathway, and sustained dysfunction of reward circuitry is associated with return to drinking behavior. We tested this hypothesis by infusing adeno-associated virus serotype 2 vector encoding human glial-derived neurotrophic factor (AAV2-hGDNF), a growth factor that enhances dopaminergic neuron function, into the VTA of four male rhesus monkeys, with another four receiving vehicle, following induction of chronic alcohol drinking. GDNF expression ablated the return to alcohol drinking behavior over a 12-month period of repeated abstinence-alcohol reintroduction challenges. This behavioral change was accompanied by neurophysiological modulations to dopamine signaling in the nucleus accumbens that countered the hypodopaminergic signaling state associated with chronic alcohol use, indicative of a therapeutic modulation of limbic circuits countering the effects of alcohol. These preclinical findings suggest gene therapy targeting relapse prevention may be a potential therapeutic strategy for AUD.

Altered Accumbal Dopamine Terminal Dynamics Following Chronic Heroin Self-Administration.

Administration of heroin results in the engagement of multiple brain regions and the rewarding and addictive effects are mediated, at least partially, through activation of the mesolimbic dopamine system. However, less is known about dopamine system function following chronic exposure to heroin. Withdrawal from chronic heroin exposure is likely to drive a state of low dopamine in the nucleus accumbens (NAc), as previously observed during withdrawal from other drug classes. Thus, we aimed to investigate alterations in NAc dopamine terminal function following chronic heroin self-administration to identify a mechanism for dopaminergic adaptations. Adult male Long Evans rats were trained to self-administer heroin (0.05 mg/kg/inf, IV) and then placed on a long access (FR1, 6-h, unlimited inf, 0.05 mg/kg/inf) protocol to induce escalation of intake. Following heroin self-administration, rats had decreased basal extracellular levels of dopamine and blunted dopamine response following a heroin challenge (0.1 mg/kg/inf, IV) in the NAc compared to saline controls. FSCV revealed that heroin-exposed rats exhibited reduced stimulated dopamine release during tonic-like, single-pulse stimulations, but increased phasic-like dopamine release during multi-pulse stimulation trains (5 pulses, 5-100 Hz) in addition to an altered dynamic range of release stimulation intensities when compared to controls. Further, we found that presynaptic D3 autoreceptor and kappa-opioid receptor agonist responsivity were increased following heroin self-administration. These results reveal a marked low dopamine state following heroin exposure and suggest the combination of altered dopamine release dynamics may contribute to increased heroin seeking.