Comparison Of Affective Analgesia And Conditioned Place Preference Following Cholinergic Activation Of

Activation of the dopaminergic mesolimbic reward circuitry that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress affective reactions to noxious stimuli (affective analgesia, AA). VTA dopamine neurons are activated via cholinergic inputs, and we have observed that microinjections of the acetylcholine agonist carbachol suppressed vocalizations of rats that occur following administration of brief (1 sec) tail-shocks (vocalization afterdischarges = VAD). VADs are a validated rodent model of pain affect. In addition, the capacity of carbachol to support reinforcement appears to be regionally dependent within VTA. Ikemoto and Wise (2002) reported that carbachol was self-administered in the posterior VTA (pVTA), but not the anterior VTA (aVTA). We have previously reported that carbachol preferentially increased the threshold current intensity for eliciting VADs in aVTA and pVTA, but not midVTA. This carbachol-induced AA is mediated by muscarinic receptors within the pVTA and by both muscarinic and nicotinic receptors within the aVTA. Using the conditioned place preference paradigm (CPP), the present study evaluated the muscarinic versus nicotinic involvement in intra-VTA carbachol-induced CPP learning by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into the VTA prior to carbachol treatment. The present study indicates that unilateral carbachol (4 µg/0.25 µl) supports the CPP learning in aVTA and pVTA, but not midVTA. Additionally, both atropine (60 µg/0.25 µl) and mecamylamine (45 µg/0.25 µl) reliably prevented the development of carbachol-induced CPP in the aVTA and pVTA. Thus, this study is the first to directly compare the extent of overlap between cholinergically mediated reward and affective analgesia within different VTA regions. The results are discussed in terms of anatomical and physiological properties of the VTA, with emphasis of cholinergically activated mesolimbic and mesocortical systems. Finally, based on two of the most prominent hypotheses regarding the role of DA in general, a framework is provided for understanding the role of DA in pain, analgesia, and reward in the context of DA function. Grant R01 NS045720 from the National Institute of Neurological Disorders and Stroke supported this research

Medications development for drug addiction and other neuropsychiatric disorders

Drug addiction and abuse especially opiate and psychostimulant abuse is a national and global crisis. IBNtxA (3-iodobenzoyl naltrexamine) is a novel mu opioid receptor (MOR) agonist, a naloxone derivative, structurally related to the classical MOR antagonist naltrexone. Recent studies suggest IBNtxA preferentially signals through truncated MOR splice variants, producing a unique pharmacological profile resulting in potent analgesia with reduced side effects. It has been found that M. vaccae has immunoregulatory effects that can prevent stress-induced exaggeration of neuroinflammation in the brain. The purpose of our pilot study is to develop medication for addiction and neuropsychiatric disorders. According to our purpose, we evaluated a range of IBNtxA doses to more fully assess its abuse liability and antiaddiction properties and the preimmunization effect of heat-killed M. vaccae on cocaine addiction. IBNtxA represents an intriguing lead compound for preclinical drug development specifically targeting MOR splice variants, potentially creating effective analgesics with reduced side effects. Furthermore, IBNtxA could have use as an adjunct therapy in agonist replacement strategies (e.g., methadone). M. vaccae might be helpful for cocaine relapse. Current collaborative efforts are aimed to find the total signaling pathways of IBNtxA and the effect of M. vaccae on cocaine self-administration, cocaine induced neuroinflammations and to keep finding medicine for neurological diseases

A competitive NMDA receptor antagonist potentiates the effects of morphine on spatial and discrimination learning

NMDA antagonists have been shown to attenuate the development of tolerance to the antinociceptive effects of morphine, but paradoxically, to potentiate the acute effects of morphine in assays of antinociception. In an effort to characterize the effects of these types of drugs on learning, morphine and the competitive NMDA antagonist, LY235959, were studied alone and in combination in two experiments. The first experiment utilized the Morris Swim Task, a procedure widely used to study spatial learning in rats. The second experiment used an olfactory discrimination procedure for rats. Both experiments involved the use of a within-subject, repeated acquisition and performance procedure (RAP). The RAP procedure allows the researcher to distinguish between a drug’s effects on learning versus more general performance effects. In both procedures, morphine produced selective impairments on acquisition, but LY235959 generally affected acquisition only at doses that also produced performance effects. Combinations of selected doses of the two drugs produced effects that suggest a potentiation of the effects that each drug produced alone

Preweanling exposure to selective catecholamine transporter inhibitors differentially effects morphine-induced antinociception in adulthood

The purpose of this project is to determine how early methylphenidate exposure alters opioid receptor functioning in adulthood. To this end, we will administer selective monoamine transporter inhibitors for dopamine and norepinephrine (GBR-12904 and atomoxetine) during preweanling period and assess opioid function in adult rats by testing morphine-induced antinociception using the hot-plate and tail-flick tasks. In order to assess the effects of methylphenidate use on brain functions during development, investigations have been conducted in rats using ages roughly analogous to early and late childhood

Behavioral and Neural Mechanisms of Serotonin Modulation of Impulsivity and Reward

Despite its prevalence in many psychiatric disorders, such as attention deficit hyperactivity disorder, suicidal depression, schizophrenia, and aggression and motivational disorders, impulsivity and its biological bases remain poorly understood. Subdivisions of impulsivity, including impulsive action (reduced response inhibition) and impulsive choice (reduced delay of gratification), sometimes present in an uncorrelated manner. This complexity renders pathological impulsivity difficult to treat, as different underlying causes likely result in different phenotypic presentations, despite being placed under one umbrella term. In order to study the behavior and biology of one particular facet of impulsivity, this dissertation utilizes the serotonin 1B receptor (5-HT1BR; an inhibitory G-protein coupled receptor) knockout mouse model, which presents with a specific elevation in impulsive action but not impulsive choice. In Chapter 1, I show that mice lacking the 5-HT1BR have increased impulsive action accompanied by enhanced motivation and responsiveness to palatable rewards, indicating that they may have dysregulation of subjective reward valuation. In Chapter 2, I then explore the 5- HT1BR knockout model from the perspective of behavioral inhibition, demonstrating that knockout mice have intact inhibitory learning despite having difficulty withhold responding for reward. Of particular interest to this particular presentation of impulsive action, therefore, is serotonin neuromodulation of reward circuitry in the brain. In Chapter 3, I first show behaviorally that normalizing reward value in 5-HT1BR knockout mice reduces impulsive action to the level of controls. Neurally, I then complete a series of experiments with targeted knockouts in reward-related brain regions, specifically projections to and from the nucleus accumbens shell, in addition to combined 5-HT1BR genetic heteroreceptor and viral autoreceptor knockout. Only combined Emx1+ heteroreceptor and autoreceptor knockout results in increased motivation and impulsivity similar to the whole brain knockout. On the other hand, combined VGAT+ heteroreceptor and autoreceptor knockout increases hedonic taste reactvity. This suggests that modified serotonin release in addition to multiple 5-HT1B heteroreceptor population losses synergistically modulate neural signaling to increase reward valuation and impulsive action. Together, these studies provide insight into the behavioral and biological bases of impulsive action and propose a framework for better understanding specific presentations of impulsivity

Effects of methamphetamine on sexual behavior

Methamphetamine (Meth) is a highly addictive psychostimulant associated with enhanced sexual desire, arousal, and sexual pleasure. Moreover, Meth abuse is frequently linked with the practice of sexual risk behavior and increased prevalence of Human Immunodeficiency Virus (HIV). Currently, the neurobiological basis for this drug-sex nexus is unknown. Moreover, there is a lack of studies investigating the effects of Meth on sexual behavior and more importantly, compulsive sex-seeking behavior, under controlled experimental settings in animal models. First, using immuhistochemistry for mating- and Meth-induced neural activation it was demonstrated that Meth administration in male rats activates neurons in brain regions of the limbic system that are involved in the regulation of sexual behavior. Specifically, Meth and mating co-activated neurons in the nucleus accumbens (NAc) core and shell, basolateral amygdala (BLA), anterior cingulate (ACA) and orbitofrontal (OFC) cortices. Second, the effects of acute or chronic administration of Meth on different aspects of sexual behavior were tested including motivation and performance, compulsive behavior, and reward. Results showed that high doses of Meth inhibited sexual motivation and performance. Next, to investigate Meth effects on compulsive sexual behavior a paradigm was established in which visceral illness induced by lithium chloride (LiCl) was paired with sexual reward. A low Meth dose (1mg/kg; s.c.) that does not impair sexual function had long-term effects on compulsive sexual behavior. Specifically, two weeks following the last Meth administration, Meth-pretreated males displayed sex-seeking behavior despite having learned the adverse consequences of mating. This effect was dependent on Meth administration being concurrent with sexual experience. Finally, using a conditioned place preference (CPP) paradigm, it was shown that concurrent Meth and sex experience was required for enhanced CPP for mating with Meth and for Meth alone. In contrast, reward for mating alone was decreased. Together, these findings illustrate that Meth can activate the same neurons as sexual behavior and in turn may alter this natural reward behavior. Moreover, these data indicate that the association between drug use and mating may be required for expression of compulsive sex behavior reported by Meth users and is correlated with increased reward seeking for concurrent Meth exposure and mating

Motivated behaviour - the role of GABA receptor subtypes in the nucleus accumbens

The role of γ-aminobutyric acid (GABA) in modulating nucleus accumbens (Acb) function was investigated using feeding in rats as a model of motivation. Feeding encompasses processes associated with ‘appetite’, ‘satiety’ and ‘reward’. Distinct neurotransmitter systems in the Acb have been demonstrated to control specific behavioural mechanisms subserving these motivational processes. The Acb has been described as an interface between ‘motivation’ and ‘action’. It is involved in the modulation of feeding, sexual behaviour, defensive behaviours and drug seeking. Over 97% of Acb neurons are GABAergic and GABA mimetics robustly increase food intake in satiated animals. One current hypothesis suggests that GABAA and GABAB receptors gate control of ingestive motor responses via the same circuit but this circuit cannot control more complex goal-directed behaviours (Kelley et al., 2005). Temporal changes in the feeding related ‘behavioural satiety sequence’ (BSS) correlate with mechanisms that override satiety. The BSS is sensitive to effects on consummatory behaviour. Satiated rats given chow following intra-Acb infusions of a GABAB receptor agonist fed voraciously and the BSS was delayed but all other behaviours were still present. The pattern was similar with fasting and a systemically administered benzodiazepine but, with a μ-opioid agonist (postulated to increase the incentive value of food), the peak in feeding was delayed. A GABAA receptor agonist induced feeding but all other behaviours were significantly reduced at all effective doses. In a second order operant schedule that independently measured appetitive and consummatory behaviour, the GABAA and opioid receptor agonists had no effect on responding but the GABAB receptor agonist increased reinforced responding in a dose dependent manner. Several other behavioural indices of motivation also increased, suggesting behaviourally selective effects. These results are inconsistent with the hypothesis described above. Intra-Acb GABA receptor subtype stimulation led to significant differences in the location and magnitude of activity in motivation related brain structures, particularly the lateral hypothalamus and amygdala, which were revealed using Fos-like immunoreactivity as a marker. The differential modulation of feeding behaviour via GABA receptor subtypes in the Acb is used to construct a modified model to explain endogenous inhibitory motivational control

Role of Dynorphin/Kappa Opioid Receptor Activity within the Extended Amygdala in Binge Alcohol Drinking

Alcohol Use Disorder (AUD) is a significant national and global public health problem. Of concern, binge drinking is the most common pattern of excessive alcohol consumption and serves as a risk factor for the development of AUD. Recent studies have implicated the dynorphin/kappa opioid receptor (DYN/KOR) neuropeptide system in this pattern of drinking but the precise circuitry mediating these effects are poorly understood. The central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) are two interconnected structures within the extended amygdala macrostructure that are rich in DYN/KOR and thought to contribute to binge drinking behavior. In the present studies, we demonstrate that KOR in the BNST contribute to excessive drinking by showing that site-specific delivery of a KOR antagonist decreased, while an agonist increased, binge-like alcohol consumption. Furthermore, we show that high levels of drinking induced by systemic administration of a KOR agonist were reversed by selective KOR blockade within the BNST. These findings suggest that KOR in the BNST promote binge drinking behavior, however, the endogenous dynorphinergic circuitry underlying this effect remains unknown. The CeA is a likely candidate in that it is involved in excessive drinking and sends dense dynorphinergic projections to the BNST (CeA-BNST-DYN+). In support of this hypothesis, we demonstrate that neuronal activity is increased within the CeA during a binge drinking session and that chemogenetic inhibition of the CeA-BNST-DYN+ pathway selectively decreased binge-like alcohol consumption. Collectively, these studies suggest that the CeA-BNST-DYN+ circuit contributes to binge-like alcohol consumption and KORs in the BNST likely mediate this effect. These studies provide valuable insight into neuronal circuitry underlying a key aspect of AUD and point to the DYN/KOR system as a potential therapeutic target for the treatment of excessive drinking