Methamphetamine and the Synthetic Cathinone 3,4-Methylenedioxypyrovalerone (MDPV) Produce Persistent Effects on Prefrontal and Striatal Microglial Morphology and Neuroimmune Signaling Following Repeated Binge-like Intake in Male and Female Rats.

Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions-the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500-1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase.

Environmental Enrichment Modulates Drug Addiction and Binge-Like Consumption of Highly Rewarding Substances: A Role for Anxiety and Compulsivity Brain Systems?

Drug addiction is a chronic disorder comprising components of both impulsivity and compulsivity in the so called "addiction cycle" which develops over time from early non-dependent, repetitive, binge-consumption to later post-dependent compulsive consumption. Thus, frequent binge-like intake is a typical pattern of excessive drug intake characteristic of the pre-dependent phase of the addiction cycle, which represent an important risk factor to develop addiction in vulnerable individuals. In this framework, it is of paramount interest to further understand the earliest stage of the addiction cycle so novel approaches would emerge aimed to control repetitive episodes of binge-consumption in non-dependent subjects, protecting vulnerable individuals from transition to dependence. Environmental enrichment (EE) is a preclinical animal model in which animals are housed under novel, social enriched conditions, which allows exercising and provides sensory and cognitive stimulation. EE promotes important improvements for a variety of cognitive processes and clear therapeutic and protective effects preventing ethanol (EtOH) and drug addiction as well. Interestingly, recent observations suggest that EE might additionally modulate binge-like intake of highly palatable caloric substances, including EtOH, which suggests the ability of EE to regulate consumption during the initial stage of the addiction cycle. We have proposed that EE protective and therapeutic effects on binge-consumption of palatable substances might primarily be mediated by the modulatory control that EE exerts on anxiety and impulsivity/compulsivity traits, which are all risk factors favoring transition to drug addiction.