Age- and sex-dependent effects of methamphetamine on cognitive flexibility and 5-HT2C receptor localization in the orbitofrontal cortex of Sprague-Dawley rats

Abstract

Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HTR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HTR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.

Effects of Withdrawal from Cocaine Self-Administration on Rat Orbitofrontal Cortex Parvalbumin Neurons ExpressingCre recombinase: Sex-Dependent Changes in Neuronal Function and Unaltered Serotonin Signaling

“…Therefore, sex-linked differences in the expression of these 5-HT 2 R subtypes could result in insensitivity to ketanserin in the male OFC PV cells. Finally, differences in 5-HT 2A versus 5-HT 2C receptor expression on OFC PV neurons between male and female rats have also been reported after methamphetamine self-administration (Hankosky et al, 2018), suggesting some sex-linked lability in the expression of 5-HT 2 R subtypes in these neurons. In addition to these differences in cellular distribution of 5-HT receptor subtypes, sexually dimorphic effects of 5-HT 2C R and 5-HT 1A R activation on cocaine selfadministration have been reported in rhesus monkeys (Collins and France, 2018).…”

“…In support of this, the deleterious effects of CSA on OFC-dependent reversal learning are reduced in mice lacking the SERT (Nonkes et al, 2013), and some cocaine-induced behavioral changes are absent in mutant mice expressing SERT with reduced affinity for this drug (Simmler et., 2017). Based on these findings, it has been hypothesized that 5-HT signaling is involved in the contribution the OFC to cognitive flexibility, and that psychostimulant exposure may disrupt this 5-HT function in this capacity (Roberts, 2011;Wright et al, 2017;Hankosky et al, 2018). In this regard, recent data also show profound changes to 5-HT signaling in OFC PyNs in rats withdrawn from CSA or yoked cocaine administration, and that this 5-HT hypofunction could be observed many weeks after withdrawal from cocaine (Wright et al, 2017).…”

AMPed-up adolescents: The role of age in the abuse of amphetamines and its consequences on cognition and prefrontal cortex development

“…Less sensitivity to METH in adolescents would mean that adolescents would need to take more METH in order to achieve a similar effect to that in adults. Indeed, we have previously reported a reduced sensitivity to several doses of METH in adolescent-onset rats compared to their adult-onset counterparts using a PR schedule (Hankosky et al, 2018b). One challenge to this interpretation is that when trained to self-administer different doses of METH (0.05, 0.08 or 0.1 mg/kg/inf) under ShA conditions there were no significant age-of-onset differences in acquisition (Hankosky et al, 2018a) or METH intake .…”

The Challenge by Multiple Environmental and Biological Factors Induce Inflammation in Aging: Their Role in the Promotion of Chronic Disease

“…However, the evaluation of the cognitive function of young drug users reveals a decreased performance compared with healthy young people. In fact, the cognitive function of young drug users is similar to that of adults older than 60 years of age ( 174 , 177 , 178 ).…”