Addiction is a chronic disease that characterize as habitual or compulsive involvement in an activity despite it¡¦s bring negative consequences. Some of psystimulants such as cocaine or amphetamine cause a strong reinforcing effects even after prolonged abstinence periods. Such illegal drugs not only hurt on the adult health but also result in fetal physiological damage. For example, that babies born to mothers who abuse with cocaine bring prematurely delivered, low birth weights, smaller head circumferences and increased heart disease in adult offspring. Mesolimbic dopamine system include nucleus accumbens (NAc) and ventral tegmental area (VTA) are critical regions for the neural adaptations that contribute to addiction. VTA that receives inputs from a large number of brain regions. For example, it receives glutamatergic inputs from prefrontal cortex, or GABAergic inputs from NAc. It has been known that VTA play a major role in the acquisition and expression of learned addictive behaviors. Results from many neuropharmacological studies in animal models indicate that exposure to cocaine or some other drugs of abuse seems to induce long-term potentiation (LTP) ¢w like changes of synaptic plasticity among neurons in VTA region. LTP was first described in hippocampus, a region that associated with memory formation, and were found widespread events in many mammalian brain sites. In the present time, theories and investigation indicated that memory and addiction might shared the similar neural circuitry and signal pathways. In general, LTP can be separate into two main phases : induction and maintenance phases. Many of molecules participate in induction phase such as calcium/calmodulin-dependent protein kinase II (CaMKII), cyclic AMP (cAMP), phosphatidylinositol 3-kinases (PI3K) and protein kinase C (PKC). However, until now there was only one molecule has been found associated with LTP maintenance¡Xprotein kinase M£a (PKM£a). PKM£a is a brain specific, constitutively active form of PKC that does not need Ca2+ or diacylglycerol (DAG) for its activation. Molecular evidences showed that PKM£a is translated uniquely by PKM£a mRNA which is generated under the control of an internal promoter in the PKC£a gene. Recently, investigators introduced a PKM£a selective inhibitor¡XZIP, to hippocampus or insular cortex both successful to eliminate long-term spatial memory or conditioned taste aversion (CTA) behavior, respectively, on rat. Therefore, exclude PKM£a by specific inhibitors and then result in abolish long-term synaptic potentiation which had already established seem to be a leading candidate for cure addiction. Here we showed that blocked of PKM£a activity in VTA dopaminergic neuron eliminated mEPSCs or AMPAR/NMDAR ratio increment elicited by cocaine. Otherwise, our results also presented that myristoylatedinhibitory peptide¢wZIP had no effect on spike timing-dependent long-term potentiation in rats previously injected with saline but remarkably restored spike timing-dependent long-term potentiation in VTA dopamine neurons in slices prepared from rats that received single or multiple cocaine exposure. Furthermore, our western blot analyses showed that both single and five consecutive cocaine injections induced a significant increase in PKM£a level in VTA or NAc. Moreover, our ex vivo cocaine incubation results indicated that multiple kinases activation or de novo protein synthesis was required for PKM£a increment. The most important, our data provided the first physiological evidence between PKM£a and drug addiction when intracranial administered specific PKM£a inhibitors to VTA reversed cocaine-induced conditioned-place preference (CPP) behavior. Finally, we investigated the behavioral effect of cocaine-induced locomotor sensitization in an open field apparatus. Our data showed that peri-adolescent (P21) rats exhibited prominently increased in either acute or repeated cocaine-induced locomotor activity than mid-adolescent (P28) and post-adolescent (P41). Interestingly, applied to high dosage cocaine (30 mg/kg) rescued the acute locomotor response in P28 rats but not behavioral sensitization. We further examined the locomotion on rats that were exposed to cocaine in utero after single or multiple cocaine injection. However, cocaine-induced increase in locomotor activity was lower in P21 rats which exposed to cocaine during pregnancy but no significantly difference in P28 rats. Surprisingly, single high dose cocaine treatment caused a marked reduction in locomotor activity on P21 rats prenatally exposed to cocaine. Otherwise, we also provided the first evidences that repeated cocaine injection in pregnant rats induced a significant decreased to KCC2 level in PFC regions prepared from P20 rat. In conclusion, results from our current studies demonstrate for the first time that persistently active PKM£a is necessary in (1) mEPSC facilitation induced by single cocaine exposure; (2) cocaine-induced enhancement in AMPAR/NMDAR ratio; (3) single or repeated cocaine-induced LTP but not in LTP induced by spike-timing stimulation; and (4) cocaine conditioned place preference in the VTA. In addition, our results also present evidence that the expression of PKM£a is increased by either single or repeated cocaine exposure. Furthermore, our behavioral or Western blotting consequence of cocaine treatment in utero was reflected by the diminishion in the sensitivity of locomotor activity in postnatal rats to cocaine and KCC2 level in PFC regions.

The ventral tegmental area (VTA) and its dopaminergic (DA) mesocorticolimbic projections are thought to be essential in the brain’s reward neurocircuitry. In humans and animal experimental subjects, mild electrical VTA stimulation increases dopamine levels and can induce euphoria. Paradoxically, aversive stimuli activate VTA neurons and forebrain DA activity, and excessive electrical stimulation of the VTA exaggerates fearfulness. Research suggests that experimental manipulation of either the amygdala or the VTA has similar effects on the acquisition and expression of Pavlovian conditioned fear. Recently it was demonstrated that electrical stimulation of the amygdala produced fear extinction deficits in rats. Fear extinction involves the progressive dissipation of conditioned fear responses by repeated non-reinforced exposure to a conditioned stimulus (CS). Maladaptive states of fear in fear-related anxiety disorders, such as post-traumatic stress disorders (PTSD) or specific phobias are thought to reflect fear extinction learning deficits. The primary purpose of the present study was to examine the effects of intra-VTA stimulation on fear extinction learning. Using fear-potentiated startle as a behavioural index of conditioned fear, it was found that 120 VTA stimulations paired or unpaired with non-reinforced CS presentations impaired the extinction of conditioned fear. This effect was not apparent in rats that received electrical stimulation of the substantia nigra (SN), suggesting that not all midbrain regions respond similarly. Electrical stimulation parameters did not have aversive affects because rats failed to show fear conditioning when electrical VTA stimulation was used as the unconditioned stimulus. Also, VTA stimulation did not alter conditioned fear expression in non-extinguished animals. Based on the results it is suggested that VTA activation disinhibited conditioned fear responding. Therefore, VTA neuronal excitation by aversive stimuli may play a role in fear-related anxiety disorders thought to reflect extinction learning deficits.

This research project investigates the long-term consequences of perinatal exposure to high-fat (HF) on the mesocorticolimbic dopamine (DA) system. Adult offspring of mothers fed a HF diet (30% fat, compared to 5% in control mothers (C)) during the last week of gestation and throughout lactation displayed decreased locomotion in response to an acute amphetamine challenge and decreased behavioral sensitization to repeated amphetamine compared to C animals. These behavioral effects were accompanied by small increases in tyrosine hydroxylase expression in the ventral tegmental area and significant increases in DA and DOPAC content in the NAc, suggesting an elevated DA tone in this target field. In the NAc, there were no significant changes in D1, D2 receptors or DA transporter (DAT) levels between diet groups. The behavioural and biochemical data were collected in adulthood, long after the termination of the diet suggesting that a HF perinatal diet is inducing permanent changes within the DA system and might contribute to the development of metabolic disturbances.

The ventral tegmental area (VTA) and its dopaminergic (DA) mesocorticolimbic projections are thought to be essential in the brain’s reward neurocircuitry. In humans and animal experimental subjects, mild electrical VTA stimulation increases dopamine levels and can induce euphoria. Paradoxically, aversive stimuli activate VTA neurons and forebrain DA activity, and excessive electrical stimulation of the VTA exaggerates fearfulness. Research suggests that experimental manipulation of either the amygdala or the VTA has similar effects on the acquisition and expression of Pavlovian conditioned fear. Recently it was demonstrated that electrical stimulation of the amygdala produced fear extinction deficits in rats. Fear extinction involves the progressive dissipation of conditioned fear responses by repeated non-reinforced exposure to a conditioned stimulus (CS). Maladaptive states of fear in fear-related anxiety disorders, such as post-traumatic stress disorders (PTSD) or specific phobias are thought to reflect fear extinction learning deficits. The primary purpose of the present study was to examine the effects of intra-VTA stimulation on fear extinction learning. Using fear-potentiated startle as a behavioural index of conditioned fear, it was found that 120 VTA stimulations paired or unpaired with non-reinforced CS presentations impaired the extinction of conditioned fear. This effect was not apparent in rats that received electrical stimulation of the substantia nigra (SN), suggesting that not all midbrain regions respond similarly. Electrical stimulation parameters did not have aversive affects because rats failed to show fear conditioning when electrical VTA stimulation was used as the unconditioned stimulus. Also, VTA stimulation did not alter conditioned fear expression in non-extinguished animals. Based on the results it is suggested that VTA activation disinhibited conditioned fear responding. Therefore, VTA neuronal excitation by aversive stimuli may play a role in fear-related anxiety disorders thought to reflect extinction learning deficits.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 5 uppsatser.

Thesis (Ph. D.)--Virginia Commonwealth University, 2005. / Prepared for: Dept. of Pharmacology and Toxicology. Bibliography: leaves 142-153.

abstract: Intermittent social defeat stress induces psychostimulant cross-sensitization, as well as long-lasting social avoidance behavior. Previous data reveal heightened expression of AMPA receptor (AMPAR) GluA1 subunits in rat ventral tegmental area (VTA), which occurs concurrently with social stress-induced amphetamine (AMPH) cross-sensitization. These studies described herein examined whether VTA GluA1 AMPARs are important for the behavioral consequences of social stress and investigated the role of the infralimbic (IL) to VTA pathway in the induction of these responses. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization without affecting social avoidance behavior, while GluA1 overexpression in VTA DA neurons mimicked the effects of stress on AMPH sensitization. Female rats were more sensitive to the effects of stress on AMPH administration than males, specifically during proestrus/estrus, which is characterized by higher circulating estradiol. Fluorescent immunohistochemistry revealed that females expressed higher GluA1 in VTA DA neurons as a result of intermittent social defeat stress, independent of estrus stage; by contrast, females during proestrus/estrus displayed higher tyrosine kinase receptor type 2 (TrkB) expression, which is the receptor for brain derived neurotrophic factor (BDNF), in VTA DA neurons, independent of stress exposure. Functional inactivation of GluA1 in VTA DA neurons prevented stress-induced AMPH sensitization and overexpression mimicked the effects of stress on AMPH sensitization. This suggests that BDNF-TrkB signaling may work concomitantly with GluA1 signaling in the VTA to drive sex-dependent differences in stress-induced locomotor sensitization effects. Optogenetic inhibition of the IL-VTA pathway in male rats prevented stress-induced AMPH sensitization compared to control animals. In addition, fluorescent immunohistochemistry displayed less Fos labeling in the nucleus accumbens (NAc) of rats with IL-VTA light inhibition compared to control animals. This suggests that the IL-VTA pathway plays a critical role in the induction of stress-induced sensitivity to AMPH, and blocking this pathway prevents mesolimbic DA signaling to the NAc. We conclude that IL glutamate projections onto GluA1-homomeric AMPA receptors in VTA DA neurons play a critical role in driving the stress-induced sensitization response in males and females. Therefore, GluA1 VTA DA neurons could potentially be a therapeutic target to prevent stress-induced drug susceptibility in the future. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2020

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