Modulation of cue value and the augmentation of heroin seeking in chronically food-restricted male rats under withdrawal.

Food restriction augments drug seeking in abstinent rats. The underlying motivational mechanisms, however, remain unclear. We hypothesized that caloric restriction enhances the incentive value attributed to drug-associated cues and, in turn, augments drug seeking. Male rats were trained to lever-press for heroin, and then moved to the animal colony for a forced-abstinence period. Rats were maintained on free access to food (Sated) or subjected to 14 days of food restriction (FDR). In a series of experiments, we assessed the effect of food-restriction on the incentive value of heroin-associated cues. Tests included performance under a progressive ratio (PR) schedule of reinforcement maintained by heroin-associated cues, acquisition of a novel operant response reinforced by drug-associated cues, effect of food-restriction on operant response reinforced by neutral cues, acquisition of a novel operant response reinforced by drug-associated or neutral cues, and the effect of food-restriction on operant response reinforced by drug-associated or neutral cues, under a discrete choice procedure. Food-restriction did not change breakpoints in PR maintained by heroin-associated cues. FDR rats acquired the novel response at a greater level compared to the Sated group. Food-restriction-induced increase in novel-response rate was observed for both heroin-paired and the neutral cue. Responding for a heroin-associated cue was greater than for the neutral cue in both Sated and FDR groups. Response rate for the neutral cue, however, was greater in the FDR versus Sated group. Our findings suggest that food restriction increases the conditioned motivational properties of environmental stimuli, including, but not exclusive to, heroin-paired cues.

Assessing the Role of Corticothalamic and Thalamo-Accumbens Projections in the Augmentation of Heroin Seeking in Chronically Food-Restricted Rats.

Drug addiction is a chronic disorder characterized by compulsive drug seeking, and involves repetitive cycles of compulsive drug use, abstinence, and relapse. In both human and animal models of addiction, chronic food restriction increases rates of relapse. Our laboratory has reported a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated controls. Recently, we reported that activation of the paraventricular nucleus of the thalamus (PVT) abolished heroin seeking in chronically food-restricted rats. However, the precise inputs and outputs of the PVT that mediate this effect remain elusive. The goal of the current study was to determine the role of corticothalamic and thalamo-accumbens projections in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 d. Next, rats were removed from the self-administration chambers and were subjected to a 14 d withdrawal period while sated (unlimited access to food) or mildly food-restricted (FDR). On day 14, rats were returned to the self-administration context for a 3 h heroin-seeking test under extinction conditions during which corticothalamic and thalamo-accumbens neural activity was altered using chemogenetics. Surprisingly, chemogenetic activation or inhibition of corticothalamic projections did not alter heroin-seeking behavior. Chemogenetic activation of thalamo-accumbens shell, but not core, projectors attenuated heroin seeking in FDR rats. The results indicate an important role for the PVT to nucleus accumbens shell projections in the augmentation of heroin seeking induced by chronic food restriction.SIGNIFICANCE STATEMENT Relapse to heroin use is one of the major obstacles in the treatment of opiate addiction. Triggers for relapse are modulated by environmental challenges such as caloric restriction. Elucidating the brain mechanisms that underlie relapse is critical for evidence-based treatment development. Here we demonstrate a critical role for the input from the paraventricular thalamus (PVT), a hub for cortical, sensory, and limbic information, to the nucleus accumbens shell (an area known to be important for reward and motivation) in the augmentation of heroin seeking in food-restricted rats. Our findings highlight a previously unknown role for the PVT in heroin seeking following a period of abstinence.

The role of the paraventricular nucleus of the thalamus in the augmentation of heroin seeking induced by chronic food restriction.

Drug addiction is a chronic disorder that is characterized by compulsive drug seeking and involves cycling between periods of compulsive drug use, abstinence, and relapse. In both human addicts and animal models of addiction, chronic food restriction has been shown to increase rates of relapse. Previously, our laboratory has demonstrated a robust increase in drug seeking following a period of withdrawal in chronically food-restricted rats compared with sated rats. To date, the neural mechanisms that mediate the effect of chronic food restriction on drug seeking have not been elucidated. However, the paraventricular nucleus of the thalamus (PVT) appears to be a promising target to investigate. The objective of the current study was to examine the role of the PVT in the augmentation of heroin seeking induced by chronic food restriction. Male Long-Evans rats were trained to self-administer heroin for 10 days. Rats were then removed from the training chambers and experienced a 14-day withdrawal period with either unrestricted (sated) or mildly restricted (FDR) access to food. On day 14, rats underwent a 1-hour heroin-seeking test under extinction conditions, during which neural activity in the PVT was either inhibited or increased using pharmacological or chemogenetic approaches. Unexpectedly, inhibition of the PVT did not alter heroin seeking in food-restricted or sated rats, while enhancing neural activity in the PVT-attenuated heroin seeking in food-restricted rats. These results indicate that PVT activity can modulate heroin seeking induced by chronic food restriction.

Augmentation of Heroin Seeking Following Chronic Food Restriction in the Rat: Differential Role for Dopamine Transmission in the Nucleus Accumbens Shell and Core.

Caloric restriction during drug abstinence increases the risk for relapse in addicts. In rats, chronic food restriction during a period of withdrawal following heroin self-administration augments heroin seeking. The mechanisms underlying this effect are largely unknown. Here, we investigated the role of nucleus accumbens (NAc) shell and core dopamine (DA) in food restriction-induced augmentation of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg/infusion) for 10 days. Next, rats were moved to the animal colony for a withdrawal period, during which rats were food restricted to 90% of their original body weight (FDR group) or given unrestricted access to food (sated group). On day 14 of food restriction, rats were returned to the operant conditioning chambers for a heroin-seeking test under extinction conditions. Extracellular DA levels were assessed using in vivo microdialysis. In separate experiments, the DA D1-like receptor antagonist SCH39166 (12.5, 25.0, or 50.0 ng/side) was administered into the NAc before the heroin-seeking test. In the NAc shell, pre-test exposure to the heroin-associated context increased DA only in FDR rats; but in the NAc core, DA increased regardless of feeding condition. Food restriction significantly augmented heroin seeking and increased DA in the NAc shell and core during the test. Intra-NAc shell administration of SCH39166 decreased heroin seeking in all rats. In contrast, in the NAc core, SCH39166 selectively decreased the augmentation of heroin-seeking induced by chronic food restriction. Taken together, these results suggest that activation of the DA D1-like receptor in the NAc core is important for food restriction-induced augmentation of heroin seeking.

Matriz óssea homóloga desmineralizada na união vertebral dorsolateral lombar em coelhos / Demineralized homologous bone matrix for lumbar dorsolateral spinal union in rabbits

Foi avaliada a atuação da matriz óssea homóloga desmineralizada (MOD) na união dorsolaterallombar, aplicada bilateralmente sobre os processos transversos de L5-L6, após sua descorticação, em 24 coelhos (grupo 1). Outros nove coelhos (grupo 2) foram submetidos apenas à descorticação dos processos transversos. Oito animais do grupo 1 e três do grupo 2 foram sacrificados às cinco, sete e nove semanas após a cirurgia e submetidos a avaliações radiográfica, histológica e por palpação. Os animais do grupo 1 tiveram a área de enxertia submetida a testes bio-mecânicos. No grupo 1, às cinco semanas, 37,5 por cento dos animais apresentaram união à palpação, que estava presente em 50por cento nas semanas seguintes. As análises radiográficas demonstraram índice de união de 25 por cento às cinco semanas, seguido por um índice de 100 por cento de pseudartrose às sete semanas e 33,4 por cento de união às nove semanas. A avaliação histológica demonstrou, predominantemente, a fragmentação seguida pela reabsorção da MOD, que foi substituída em quase sua totalidade por tecido conjuntivo fibroso. Quando houve união vertebral, a formação óssea endocondral se deu a partir dos processos transversos descoticados. No grupo 2, na avaliação radiográfica foi observada pequena reação periosteal local, não apresentando qualquer sinal de união nas demais análises. As evidências histológicas demonstraram que a MOD comportou-se como agente osteocondutor. O teste de tração demonstrou diferença significativa, referente à força e rigidez, entre os seg- mentos operados e os adjacentes. Evidências radiográficas, mecânicas e histológicas demonstraram que a matriz óssea homóloga desmineralizada de coelhos é ineficaz, quando utilizada isoladamente, na determinação de união vertebral dorsolaterallombar estável em coelhos

Autoenxerto de crista ilíaca de coelhos na união vertebral dorsolateral lombar / Iliac crest autograft in rabbit dorsolateral spinal fusion

Foi realizada artrodese dorsolateral das vértebras lombares L5-L6 de coelhos, avaliando-se a eficácia do autoenxerto da crista ilíaca na promoção de união vertebral. Foram utilizados 33 coelhos da raça Nova Zelândia Branco, distribuídos em dois grupos, com nove indivíduos no grupo 1 (G1), submetidos a descorticação bilateral dos processos transversos; e vinte e quatro indivíduos no grupo 2 (G2), que receberam 2g de autoenxerto da crista ilíaca sobre a área de descorticação. Três coelhos do G1 e oito do G2 foram submetidos à eutanásia as cinco, sete e nove semanas após o ato operatório e à avaliações por palpação, radiográfica e histológica no local do procedimento. Testes biomecânicos para avaliação de força e rigidez da união foram realizados somente nos animais do G2 e as vértebras adjacentes não operadas, serviram de controle. Os animais do G1 apresentaram mobilidade normal à palpação do segmento operado em todos os momentos de avaliação e não apresentaram evidência radiográfica de união. Na avaliação histológica foi observada discreta reação periosteal, sem evidências de formação de ponte óssea. No G2, as avaliações por palpação e radiográficas evidenciaram indícios de união óssea as cinco semanas, intensificando-se ao longo das semanas de avaliação. Na análise histológica foi observada reabsorção de fragmentos ósseos as cinco semanas, predominância de trabéculas ósseas e corações condróides, além de suprimento sanguíneo abundante as sete semanas e osteointegração em todo leito de enxertia as nove semanas, com predomínio de formação óssea endocondral. Os testes biomecânicos evidenciaram aumento da força e rigidez da massa óssea ao longo do tempo de avaliação. Quando foi realizada comparação das vértebras tratadas e não tratadas, os índices de união foram maiores em todos os momentos, no grupo tratado. Com os resultados foi possível concluir que alta percentagem de união vertebral foi conseguida quando o osso autógeno da crista ilíaca foi utilizado como material de enxertia em coelhos.