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Intravenous self-administration (IVSA) is a behavioral method of voluntary drug intake in animal models which is used to study the reinforcing effects of drugs of abuse. It is considered to have greater face validity in the study of substance use and abuse than other assays, and thus, allows for valuable insight into the neurobiological basis of addiction, and the development of substance abuse disorders. The technique typically involves surgically inserting a catheter into the jugular vein, which enables the infusion of drug solution after the performance of a desired operant behavior. Two nose- poke ports or levers are offered as manipulanda and are randomly assigned as active (reinforced) or inactive (non-reinforced) to allow for the examination of discrimination in the assessment of learning. Here, we describe our methodological approach to this assay in a mouse model, including construction and surgical implantation of a jugular vein catheter, set up of operant chambers, and considerations during each phase of the operant task. [ABSTRACT FROM AUTHOR]

The fragile X mental retardation protein (FMRP), an RNA‐binding protein, regulates cocaine‐induced neuronal plasticity and is critical for the normal development of drug‐induced locomotor sensitization, as well as reward‐related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing a cocaine intravenous self‐administration (IVSA) assay in Fmr1 knockout (KO) and wild‐type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose–response testing. Later, when given access to the original acquisition dose under increasing fixed ratio (FR) schedules of reinforcement (FR1, FR3, and FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, similar deficits are not present in operant conditioning using a palatable food reinforcer, indicating that our results do not represent broad learning or reward‐related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity‐regulated cytoskeleton‐associated protein (Arc), to be significantly reduced in synaptic cellular fractions prepared from the nucleus accumbens of Fmr1 KO, compared with WT, mice following operant tasks reinforced with cocaine but not food. Overall, our findings suggest that FMRP facilitates adjustments in drug self‐administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice may implicate Arc, along with FMRP, in behavioral shifts that occur in drug taking when drug availability is altered. [ABSTRACT FROM AUTHOR]

Abstract: Adolescent nicotine exposure is associated with long-term use, and it has been suggested that this vulnerability to addiction may relate to lasting anxiogenic effects of the drug. However, few studies have addressed long-term effects of adolescent nicotine, and fewer yet have compared adolescent to adult exposure. Male and female Long-Evans rats continuously received nicotine bitartrate or sodium tartrate via osmotic mini-pumps over 15 days either during adolescence (p28–42) or adulthood (p85–99). Initial nicotine dose (free base) was either low (1 mg/kg/day) or high (2 mg/kg/day). Open field behavior and fear conditioning were assessed in adulthood, 1 month post-dosing. Animals pretreated with nicotine during adolescence showed less center time in a novel open field than sham controls. Conversely, the two nicotine doses differentially affected fear conditioning. Animals pretreated with low nicotine during adolescence demonstrated superior acquisition of the task compared to sham control animals; however, unlike either high nicotine-pretreated or sham control animals, they failed to extinguish the learned behavior. In contrast, animals pretreated during adulthood did not behave significantly different from sham controls on either task. Overall, nicotine-pretreatment during adolescence induced effects on behaviors related to fear and anxiety in adulthood, while comparable pretreatment during adulthood failed to produce significant residual effects. [Copyright &y& Elsevier]

Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder. [ABSTRACT FROM AUTHOR]

Abstract: The objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long–Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps. At p144, 75 days after conclusion of nicotine administration, brains were processed for Golgi–Cox staining. Medium spiny neurons from the nucleus accumbens shell were digitally reconstructed. It was found that neurons from nicotine-treated animals possessed significantly longer dendrites and a greater number of dendritic segments than control animals. A branch order analysis indicated that differences in dendritic length and segment number were most pronounced in third and fourth order segments. A subsequent behavioral experiment suggests that the observed anatomical changes are associated with enduring psychomotor differences. These findings indicate that periadolescent exposure to nicotine can result in long-lasting structural changes in the nucleus accumbens shell and are consistent with behavioral data suggesting that adolescent nicotine exposure may result in vulnerability to nicotine addiction in adulthood. [Copyright &y& Elsevier]