operant conditioning [keywords]
- Reinforcing Effects of Cathinone NPS in the Intravenous Drug Self-Administration Paradigm. [JOURNAL ARTICLE]
- Curr Top Behav Neurosci 2016 Jul 19.
Since the mid- to late 2000s, there has been a dramatic rise in the use and abuse of synthetic derivatives of cathinone, a stimulant alkaloid found in the African shrub Catha edulis. Cathinone novel psychoactive substances (NPS), also referred to as synthetic cathinones or "bath salt"-type drugs, have gained popularity among drug users due to their potency, low cost, ease of procurement, and diverse array of evolving chemical structures. While the ability of cathinone NPS to produce psychotomimetic effects, multiple organ system toxicity, and death in humans is well documented, there has been limited scientific investigation into the reinforcing effects and abuse liability of these drugs. In this chapter, we will summarize the existing literature on the reinforcing effects of cathinone NPS in rodents using the intravenous self-administration (IVSA) paradigm. We will also compare the ability of cathinone NPS to serve as reinforcers to that of classical psychostimulants such as cocaine, methamphetamine, and methylenedioxymethamphetamine (MDMA). The chapter will conclude with a summary and indications for future avenues of research on cathinone NPS.
- Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss. [Journal Article]
- Mol Metab 2016 Jul; 5(7):566-79.
Appetitive responses to weight loss are mediated by a nutrient-sensing neural network comprised of melanocortin neurons. The role of neural melanocortin-3 receptors (MC3R) in mediating these responses is enigmatic. Mc3r knockout mice exhibit a paradoxical phenotype of obesity and reduced feeding-related behaviors in situations of nutrient scarcity. Here we examined whether MC3Rs expressed in mesolimbic neurons regulate feeding-related motivational responses.Interactions between Mc3r genotype, cognitive function and energy balance on food self-administration were assessed using operant conditioning with fixed- and progressive ratio (FR1/PR1) settings. Inhibition of Mc3r transcription by a loxP-flanked transcriptional blocker (TB) in C57BL/6JN mice (Mc3r (TB/TB) ) was reversed in mesolimbic neurons using DAT-Cre (DAT-MC3R).Caloric restriction (CR) caused 10-15% weight loss and increased motivation to acquire food rewards during training sessions. c-Fos-expression in the nucleus accumbens was increased 1 h following food presentation. While exhibiting weight loss, total food self-administration, enhanced motivation to self-administer food rewards in training sessions held during CR and c-Fos-activation in the nucleus accumbens following re-feeding were all markedly attenuated in Mc3r (TB/TB) mice. In contrast, cognitive abilities were normal in Mc3r (TB/TB) mice. Total food self-administration during FR1 sessions was not rescued in DAT-MC3R mice, however enhanced motivational responses to self-administer food rewards in PR1 conditions were restored. The nutrient-partitioning phenotype observed with Mc3r-deficiency was not rescued in DAT-MC3R mice.Mesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning.
- The effects of sex, estrous cycle, and social contact on cocaine and heroin self-administration in rats. [JOURNAL ARTICLE]
- Psychopharmacology (Berl) 2016 Jul 2.
Preclinical studies indicate that gonadal hormones are important determinants of drug self-administration. To date, little is known about the influence of sex and estrous cycle on drug self-administration in ecologically relevant social contexts.The objective of this study was to examine the role of sex and estrous cycle in a rat model during cocaine and heroin self-administration with male-female and female-female social dyads.Male and female virgin rats were trained to self-administer cocaine and heroin in operant conditioning chambers that permitted two rats to self-administer concurrently, but prevented physical contact. Experiment 1 examined cocaine self-administration on a progressive ratio schedule in male-female dyads. Experiments 2 and 3 examined heroin self-administration on a fixed ratio schedule in male-female dyads at constant and varying doses, respectively. Experiment 4 examined heroin self-administration in female-female dyads on a fixed ratio schedule.Cocaine-maintained breakpoints increased by ∼17 % in females during estrus, but remained consistent in males. Heroin self-administration decreased by ∼70 % during proestrus in females whether they were isolated, housed with males, or housed with females. Heroin self-administration was lower in males than females under some conditions and was not consistently associated with the responding of females.Cocaine and heroin self-administration is influenced by the estrous cycle in females when in the presence of a male partner. As a novel finding, these data illustrate that heroin self-administration is reduced in females during proestrus regardless of the social context tested. Finally, these data suggest that drug self-administration in males is only minimally influenced by the hormonal status of a female partner.
- The Dark Side of Addiction: The Horsley Gantt to Joseph Brady Connection. [JOURNAL ARTICLE]
- J Nerv Ment Dis 2016 Jun 28.
W. Horsley Gantt and Joseph V. Brady laid a rich foundation for understanding the concept of emotion, derived from 2 prominent traditions of physiology and psychology: classic conditioning and operant conditioning, respectively. This framework guided my fierce interest in motivation in general and the interaction between reward and stress, which began at John Hopkins with my thesis work under the guidance of Drs. Zoltan Annau, Solomon Synder, and Joseph Brady, among many others. Using the study of the neurobiology of addiction as a framework, I argue that drug addiction not only involves positive reinforcement associated with the rewarding effects of drugs of abuse but also involves another major source of reinforcement, specifically negative reinforcement driven by negative emotional states (termed the "dark side" of addiction). Excessive activation of the brain reward systems leads to antireward or a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of the brain stress systems, both of which may be neurobiologically linked. Understanding the neuroplasticity of the neurocircuitry that comprises the negative reinforcement associated with addiction is a key to understanding negative emotional states in general and their pathophysiology.
- Prepulse inhibition of the acoustic startle reflex vs. auditory brainstem response for hearing assessment. [JOURNAL ARTICLE]
- Hear Res 2016 Jun 24.:80-93.
The high prevalence of noise-induced and age-related hearing loss in the general population has warranted the use of animal models to study the etiology of these pathologies. Quick and accurate auditory threshold determination is a prerequisite for experimental manipulations targeting hearing loss in animal models. The standard auditory brainstem response (ABR) measurement is fairly quick and translational across species, but is limited by the need for anesthesia and a lack of perceptual assessment. The goal of this study was to develop a new method of hearing assessment utilizing prepulse inhibition (PPI) of the acoustic startle reflex, a commonly used tool that measures detection thresholds in awake animals, and can be performed on multiple animals simultaneously. We found that in control mice PPI audiometric functions are similar to both ABR and traditional operant conditioning audiograms. The hearing thresholds assessed with PPI audiometry in sound exposed mice were also similar to those detected by ABR thresholds one day after exposure. However, three months after exposure PPI threshold shifts were still evident at and near the frequency of exposure whereas ABR thresholds recovered to the pre-exposed level. In contrast, PPI audiometry and ABR wave one amplitudes detected similar losses. PPI audiometry provides a high throughput automated behavioral screening tool of hearing in awake animals. Overall, PPI audiometry and ABR assessments of the auditory system are robust techniques with distinct advantages and limitations, which when combined, can provide ample information about the functionality of the auditory system.
- Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories. [Journal Article]
- J Neurosci 2016 Jun 22; 36(25):6691-703.
In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area.A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area.
- Impaired executive functions in experimental model of temporal lobe epilepsy. [Journal Article]
- Arq Neuropsiquiatr 2016 Jun; 74(6):470-7.
The present study aimed to investigate cognitive and behavioural changes consistent with attention deficit hyperactivity disorder (ADHD -like behavior in male Wistar rats with temporal lobe epilepsy (TLE).Male Wistar rats at 25 day of age were submitted to animal model of TLE by pilocarpine injection (350 mg/kg, ip) and a control group received saline 0.9%. The animals were continuously video monitored up to the end of experiments. The behavioural tests (open field, elevated plus maze and operant conditioning box) started from 60 days postnatal.Animals with TLE exhibited elevated locomotor activity, reduced level of anxiety-related behavior, impulsivity and impaired visuospatial working memory.Taken as a whole, we concluded that animals with TLE exhibited some cognitive and behavioural changes consistent with ADHD-like behavior.
- Prior alcohol consumption does not impair go/no-go discrimination learning, but causes over-responding on go trials, in rats. [JOURNAL ARTICLE]
- Behav Brain Res 2016 Jun 17.:272-278.
Prior alcohol use is associated with impaired response inhibition in humans, including in laboratory go/no-go discrimination tasks. In two experiments, we determined whether chronic intermittent access to alcohol would alter go/no-go discrimination learning. Rats received 4-6 weeks of chronic intermittent access to 20% alcohol (alone or accompanied by saline or 1.5g/kg alcohol injections) or water. Rats then began discrimination training 4-5days after the end of the alcohol access. Each lever was available for 40s with one lever intermittently reinforced ("active lever") and the other lever non-reinforced ("inactive lever"). The rats given access to alcohol without concurrent alcohol injections drank ∼10g/kg/24-h on average during the last three weeks of alcohol access. The groups given alcohol injections (Alcohol+Injection groups) exhibited suppressed drinking, but the Alcohol+Injection groups exhibited higher blood alcohol spikes than all other alcohol groups (195 vs. 85-90mg/dl, respectively). We found no evidence for impaired go/no-go discrimination learning in either experiment. However, the alcohol access groups with moderate-to-high average alcohol consumption (>3g/kg/24-h) exhibited over-responding to the active lever compared to the water-only groups. One group given alcohol injections (Alcohol+Injection group) that exhibited very low voluntary drinking (<1g/kg/24-h) did not exhibit the over-responding effect, suggesting that the total 24-h alcohol dose matters more than short-lived blood alcohol spikes. Our findings are in accord with previous research showing that repeated alcohol withdrawal causes over-responding for responses that lead to limited reinforcement. Future work will determine the psychological and neurobiological basis of this behavioral change.
- Commentary: Behavior analysis and behavioral neuroscience. [Journal Article]
- Front Hum Neurosci 2016.:256.
- Cross-modal object recognition and dynamic weighting of sensory inputs in a fish. [Journal Article]
- Proc Natl Acad Sci U S A 2016 Jul 5; 113(27):7638-43.
Most animals use multiple sensory modalities to obtain information about objects in their environment. There is a clear adaptive advantage to being able to recognize objects cross-modally and spontaneously (without prior training with the sense being tested) as this increases the flexibility of a multisensory system, allowing an animal to perceive its world more accurately and react to environmental changes more rapidly. So far, spontaneous cross-modal object recognition has only been shown in a few mammalian species, raising the question as to whether such a high-level function may be associated with complex mammalian brain structures, and therefore absent in animals lacking a cerebral cortex. Here we use an object-discrimination paradigm based on operant conditioning to show, for the first time to our knowledge, that a nonmammalian vertebrate, the weakly electric fish Gnathonemus petersii, is capable of performing spontaneous cross-modal object recognition and that the sensory inputs are weighted dynamically during this task. We found that fish trained to discriminate between two objects with either vision or the active electric sense, were subsequently able to accomplish the task using only the untrained sense. Furthermore we show that cross-modal object recognition is influenced by a dynamic weighting of the sensory inputs. The fish weight object-related sensory inputs according to their reliability, to minimize uncertainty and to enable an optimal integration of the senses. Our results show that spontaneous cross-modal object recognition and dynamic weighting of sensory inputs are present in a nonmammalian vertebrate.