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Behavioral sensitization is accompanied by an enhancement in amphetamine-stimulated dopamine release from striatal tissue in vitro

Behavioral sensitization to amphetamine is a complex phenomenon that engages several neurotransmitter systems and brain regions. While dysregulated signaling in the mesolimbic dopamine system repeatedly has been linked to behavioral sensitization, later research has implicated dorsal striatal circuits and GABAergic neurotransmission in contributing to behavioral transformation elicited by amphetamine. The aim of this study was thus to determine if repeated amphetamine exposure followed by abstinence would alter inhibitory neurotransmission in dorsal striatal subregions. To this end, male Wistar rats received amphetamine (2.0 mg/kg) in an intermittent manner for a total of five days. Behavioral sensitization to amphetamine was measured in locomotor-activity boxes, while neuroadaptations were recorded in the dorsolateral (DLS) and dorsomedial striatum (DMS) using ex vivo electrophysiology at different timepoints of amphetamine abstinence (2 weeks, 4–5 weeks, 10–11 weeks). Data show that repeated drug-exposure produces behavioral sensitization to the locomotor-stimulatory properties of amphetamine, which sustains for at least ten weeks. Electrophysiological recordings demonstrated a long-lasting suppression of evoked population spikes in both striatal subregions. Furthermore, following ten weeks of abstinence, the responsiveness to a dopamine D2 receptor agonist was significantly impaired in brain slices from rats previously receiving amphetamine. However, neither the frequency nor the amplitude of spontaneous inhibitory currents was affected by treatment at any of the time points analyzed. In conclusion, passive administration of amphetamine initiates long-lasting neuroadaptations in brain regions associated with goal-directed behavior and habitual performance, but these transformations do not appear to be driven by changes in GABAergic neurotransmission.

One of the most studied neurons in the field of addiction are those located in the ventral tegmental area (VTA) that utilize dopamine (DA) as a signaling molecule. VTA DA neurons play a critical role in animal and human behaviors related to motivation, including a role in mediating the rewarding effects of drugs of abuse. In the present chapter, we provide an overview on research leading to current conceptualization of the role of the DA system in drug addiction, including recent findings obtained with newly developed technology. In the first part of this chapter, we summarize converging evidence on the involvement of VTA DA neurons in drug-reinforced behaviors in the context of an anatomically and functionally heterogeneous VTA. We next describe finding on the regulatory activity that multiple brain areas exert on VTA DA neurons, as well as plastic and molecular drug-induced changes within VTA DA neurons. These drug-induced changes may outlast the presence of the drug in the organism and contribute to modifications in neuronal circuits that subserve the transition from recreational to compulsive drug use. Towards the end of this chapter, we provide an overview on the participation of VTA DA neurons in the different stages of the recurring addiction cycle: binge/intoxication stage (studied with reinforcement in animal models), withdrawal/negative affect stage and preoccupation/anticipation of obtaining the drug (studied with reinstatement in animal models). We also cover findings on the role of specific axonal projections of VTA DA neurons in the different stages of the recurring addiction cycle. After the integration of an impressive contribution of classical and recent findings, we have a better understanding of the converging acute or chronic effects that drugs of abuse have on VTA DA neurons and their target brain regions to modulate drug seeking and taking behaviors.

The striatum is a subcortical structure that serves as the primary input nucleus of the basal ganglia. Through its diverse arrangement of afferent and efferent connections, the striatum regulates the expression of actions by integrating motor commands with cognitive, motivational, and emotional input (Haber, 2016). By merging internal value with external cues, the striatum learns which actions, and in which context, result in the acquisition of a reward and reinforces those actions to guide future reward-driven behavior. If the reward being sought is a drug of abuse, the striatum pathologically promotes actions that lead to acquisition of the substance. Consider the process of drinking a few beers after a stressful week of work. Execution of this behavior requires the selection of a motor plan motivated by an internal drive (e.g., to reduce stress) and the integration of the reward history of that motor action (e.g., drinking previously was rewarding). Once this motor program is learned, through repeated execution and reinforcement, this behavior becomes engrained in striatal circuits and can be elicited almost automatically by sensory cues in the environment—even in the face of known negative consequences (e.g., drinking previously led to poor work performance). As such, the striatum plays a fundamental role in the decisions and actions we make every day, and by extension how we define ourselves through those actions.

Decades of research have described the importance of corticotropin-releasing factor (CRF) signaling in alcohol addiction, as well as in commonly co-expressed neuropsychiatric diseases, including anxiety and mood disorders. However, CRF signaling can also acutely regulate binge alcohol consumption, anxiety, and affect in non-dependent animals, possibly via modulation of central monoaminergic signaling. We hypothesize that basal CRF tone is particularly high in animals and humans with an inherent propensity for high anxiety and alcohol consumption, and thus these individuals are at increased risk for the development of alcohol use disorder and comorbid neuropsychiatric diseases. The current review focuses on extrahypothalamic CRF circuits, particularly those stemming from the bed nucleus of the stria terminalis (BNST), found to play a role in basal phenotypes, and examines whether the intrinsic hyperactivity of these circuits is sufficient to escalate the expression of these behaviors and steepen the trajectory of development of disease states. We focus our efforts on describing CRF modulation of biogenic amine neuron populations that have widespread projections to the forebrain to modulate behaviors, including alcohol and drug intake, stress reactivity, and anxiety. Further, we review the known sex differences and estradiol modulation of these neuron populations and CRF signaling at their synapses to address the question of whether females are more susceptible to the development of comorbid addiction and stress-related neuropsychiatric diseases because of hyperactive extrahypothalamic CRF circuits compared to males.

Repeated intermittent exposure to cocaine results in the neurochemical sensitization of dopamine (DA) transmission within the nucleus accumbens (NAc). Indeed, the excitability of DA neurons in the ventral tegmental area (VTA) is enhanced within hours of initial psychostimulant exposure. However, it is not known if this is accompanied by a comparably rapid change in the ability of cocaine to increase extracellular DA concentrations in the ventral striatum. To address this question we used fast-scan cyclic voltammetry (FSCV) in awake-behaving rats to measure DA responses in the NAc shell following an initial intravenous cocaine injection, and then again 2-h later. Both injections quickly elevated DA levels in the NAc shell, but the second cocaine infusion produced a greater effect than the first, indicating sensitization. This suggests that a single injection of cocaine induces sensitization-related plasticity very rapidly within the mesolimbic DA system.

The synthetic cathinone derivative, mephedrone, is a controlled substance across Europe. Its effects have been compared by users to 3,4-methylenedioxymethamphetamine (MDMA), but little data exist on its pharmacological properties. This study compared the behavioural and neurochemical effects of mephedrone with cathinone and MDMA in rats. Young-adult male Lister hooded rats received i.p. cathinone (1 or 4 mg/kg), mephedrone (1, 4 or 10 mg/kg) or MDMA (10 mg/kg) on two consecutive days weekly for 3 weeks or as a single acute injection (for neurochemical analysis). Locomotor activity (LMA), novel object discrimination (NOD), conditioned emotional response (CER) and prepulse inhibition of the acoustic startle response (PPI) were measured following intermittent drug administration. Dopamine, 5-hydroxytryptamine (5-HT) and their major metabolites were measured in striatum, frontal cortex and hippocampus by high performance liquid chromatography 7 days after intermittent dosing and 2 h after acute injection. Cathinone (1, 4 mg/kg), mephedrone (10 mg/kg) and MDMA (10 mg/kg) induced hyperactivity following the first and sixth injections and sensitization to cathinone and mephedrone occurred with chronic dosing. All drugs impaired NOD and mephedrone (10 mg/kg) reduced freezing in response to contextual re-exposure during the CER retention trial. Acute MDMA reduced hippocampal 5-HT and 5-HIAA but the only significant effect on dopamine, 5-HT and their metabolites following chronic dosing was altered hippocampal 3,4-dihydroxyphenylacetic acid (DOPAC), following mephedrone (4, 10 mg/kg) and MDMA. At the doses examined, mephedrone, cathinone, and MDMA induced similar effects on behaviour and failed to induce neurotoxic damage when administered intermittently over 3 weeks.