Development Of Cocaine Sensitization Research Articles

Pharmacological NOS-1 Inhibition Within the Hippocampus Prevented Expression of Cocaine Sensitization: Correlation with Reduced Synaptic Transmission.

Behavioral sensitization to psychostimulants hyperlocomotor effect is a useful model of addiction and craving. Particularly, cocaine sensitization in rats enhanced synaptic plasticity within the hippocampus, an important brain region for the associative learning processes underlying drug addiction. Nitric oxide (NO) is a neurotransmitter involved in both, hippocampal synaptic plasticity and cocaine sensitization. It has been previously demonstrated a key role of NOS-1/NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic plasticity. The aim of the present investigation was to determine whether NOS-1 inhibition after development of cocaine sensitization was able to reverse it, and to characterize the involvement of the hippocampus in this phenomenon. Male Wistar rats were administered only with cocaine (15mg/kg/dayi.p.) for 5days. Then, animals received 7-nitroindazole (NOS-1 inhibitor) either systemically for the next 5days or a single intra-hippocampal administration. Development of sensitization and its expression after withdrawal were tested, as well as threshold for long-term potentiation in hippocampus, NOS-1, and CREB protein levels and gene expression. The results showed that NOS-1 protein levels and gene expression were increased only in sensitized animals as well as CREB gene expression. NOS-1 inhibition after sensitization reversed behavioral expression and the highest level of hippocampal synaptic plasticity. In conclusion, NO signaling within the hippocampus is critical for the development and expression of cocaine sensitization. Therefore, NOS-1 inhibition or NO signaling pathways interferences during short-term withdrawal after repeated cocaine administration may represent plausible pharmacological targets to prevent or reduce susceptibility to relapse.

Involvement of nNOS/NO/sGC/cGMP signaling pathway in cocaine sensitization and in the associated hippocampal alterations: does phosphodiesterase 5 inhibition help to drug vulnerability?

Repeated cocaine administration induces behavioral sensitization in about 50% of treated animals. Nitric oxide could be involved in the acquisition and maintenance of behavioral cocaine effects, probably by activation of neuronal nitric oxide synthase (nNOS)/NO/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) signaling pathway, since inhibition of the nNOS enzyme attenuates development of sensitization in rats. On the other hand, increased cGMP availability by phosphodiesterase 5 inhibitors has been correlated to the misuse and recreational use of these agents and also to the concomitant use with illicit drugs in humans. Hippocampus is an important brain region for conditioning to general context previously associated to drug availability, influencing drug-seeking behavior and sensitization. Moreover, cocaine and other drugs of abuse can affect the strength of glutamate synapses in this structure, lastly modifying neuronal activity in main regions of the reward circuitry. The objective of this study is to determine whether the pharmacological manipulation of nNOS/NO/sGC/cGMP signaling pathway altered changes induced by repeated cocaine exposure. The present investigation showed a relationship between behavioral cocaine sensitization, reduced threshold to generate long-term potentiation (LTP) in hippocampal dentate gyrus, and increased nNOS activity in this structure. However, when nNOS or sGC were inhibited, the number of sensitized animals was reduced, and the threshold to generate LTP was increased. The opposite occurred when cGMP availability was increased. We demonstrate a key role of the nNOS activity and NO/sGC/cGMP signaling pathway in the development of cocaine sensitization and in the associated enhancement of hippocampal synaptic transmission.

Development of cocaine sensitization before pregnancy affects subsequent maternal retrieval of pups and prefrontal cortical activity during nursing

Pups are a highly rewarding stimulus for early postpartum rats. Our previous work supports this notion by showing that suckling activates the mesocorticolimbic system in mothers. In the present study, we tested whether development of behavioral sensitization to cocaine before pregnancy affects the neural response to pups during the early postpartum days (PD). Virgin rats were repeatedly administered cocaine for 14 days (15 mg kg −1) and withdrawn from treatment during breeding and pregnancy. The neural response to suckling was measured at PD 4–8 using blood-oxygen-level-dependent (BOLD) MRI or microdialysis. Our results show that BOLD activation in the medial prefrontal cortex (PFC), septum and auditory cortex was curtailed in cocaine-sensitized dams. No differences between cocaine sensitized and saline control dams were observed in the nucleus accumbens, olfactory structures, or in 48 additional major brain regions that were analyzed. Baseline, but not pup-stimulated, dopamine (DA) levels in the medial PFC were lower in cocaine-sensitized dams than in controls. When tested for maternal behaviors, cocaine-sensitized dams showed significantly faster retrieval of pups without changes in other maternal behaviors such as grouping, crouching and defending the nest. Taken together, the present findings suggest that maternal motivation to retrieve pups was enhanced by repeated cocaine exposure and withdrawal, a result reminiscent of ‘cross-sensitization’ between the drug and a natural reward. Changes in retrieval behavior in cocaine-sensitized mothers might be associated with a hypo-responsive medial PFC.

Ribozyme attenuates reward to morphine in mice by interfering with mper1 gene expression

Studies on Drosophila melanogaster have shown that the period gene, a circadian clock gene and essential component of the underlying molecular feedback loop, can influence behavioural responses to cocaine. The mouse homologues, mPer1 and mPer2, were also shown to modulate cocaine sensitization and reward. Reportedly, normal expression of the per gene is important for the development of cocaine sensitization in Drosophila and in the mouse. This study examines the role of mPer1 on morphine addiction by applying a ribozyme to interfere with the expression of mPer1 in the central nervous system of mice. A plasmid based on pcDNA3.1 was constructed, using the expression of a hammerhead ribozyme that can selectively cleave the mPer1 mRNA. The ribozyme's presence was associated with a statistically significant reduction in mPer1 mRNA. Mice treated with the ribozyme and morphine synchronously did not show any preference for the morphine-paired side, whereas the control mice did. These results suggest that mPer1 is involved in the reward formation to morphine.

Effects of cocaine‐induced behavioural sensitization on GABA transmission within rat medial prefrontal cortex

Studies support the involvement of mPFC dopaminergic and glutamatergic systems in the development of cocaine sensitization. GABA is known to modulate dopamine and glutamatergic systems in the mPFC. In addition, recent reports have suggested that cocaine sensitization might be associated with a decrease in GABAB receptor responsiveness in the mPFC. Hence, in vivo microdialysis of the mPFC was performed to examine the effects on extracellular GABA levels within the mPFC of a cocaine challenge subsequent to repeated cocaine administration. Male Sprague-Dawley rats were given four daily injections of saline (1.0 mL/kg, i.p.) or cocaine (15 mg/kg, i.p.) and challenged with the same dose of saline or cocaine 1, 7 or 28 days later. Acute cocaine produced a motor-stimulant response that was significantly augmented in repeated cocaine animals at all withdrawal time points. Moreover, sensitized animals exhibited a significant increase in extracellular GABA levels after 1 and 7 days but not 28 days following repeated cocaine exposure. These data suggest that cocaine-induced sensitization is associated with a transient increase in mPFC GABA transmission.

Cortical Mechanisms of Cocaine Sensitization

Behavioral sensitization is the augmented motor-stimulant response that occurs with repeated, intermittent exposure to most drugs of abuse, including cocaine. Sensitization, which is a long-lasting phenomenon, is thought to underlie drug craving and relapse to drug use. Much research has been conducted to determine the neural mechanisms of sensitization. The bulk of this effort has focused on the nucleus accumbens and ventral tegmental area (VTA) that comprise a portion of the mesolimbic dopamine system. Recently, studies have begun to also explore the role of the medial prefrontal cortex (mPFC) in sensitization, in part because this region provides glutamatergic innervation to the VTA and nucleus accumbens. The present review will coalesce these studies into a working hypothesis that states that cocaine sensitization results from a decrease in inhibitory modulation of excitatory transmission from the mPFC to the VTA and nucleus accumbens. The discussion will revolve around how repeated cocaine exposure alters dopamine, gamma-aminobutyric acid (GABA), and glutamate regulation of pyramidal cell activity. It will be proposed that cocaine-induced alterations in cortical transmission occur in two phases. During early withdrawal from repeated cocaine exposure, changes in neurotransmitter release are thought to underlie the decreased inhibitory modulation of pyramidal projection neurons. Following more prolonged withdrawal, the attenuation in inhibitory transmission appears to occur at the receptor level. A model will be presented that may serve to direct future studies on the involvement of the mPFC in the development of cocaine sensitization, which ultimately could lead to development of pharmacotherapies for cocaine addiction.

Effects of repeated cocaine on medial prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system.

Increased excitatory output from medial prefrontal cortex is an important component in the development of cocaine sensitization. Activation of GABAergic systems in the prefrontal cortex can decrease glutamatergic activity. A recent study suggested that sensitization might be associated with a decrease in GABAB receptor responsiveness in the medial prefrontal cortex. Therefore, the present study examined whether repeated exposure to cocaine-modified neurochemical changes in the mesocorticolimbic dopamine system induced by infusion of baclofen into the medial prefrontal cortex. In vivo microdialysis studies were conducted to monitor dopamine, glutamate and GABA levels in the medial prefrontal cortex and glutamate levels in the ipsilateral nucleus accumbens and ventral tegmental area during the infusion of baclofen into medial prefrontal cortex. Baclofen minimally affected glutamate levels in the medial prefrontal cortex, nucleus accumbens or ventral tegmental area of control animals, but dose-dependently increased glutamate levels in each of these regions in animals sensitized to cocaine. This effect was not the result of changes in GABAB receptor-mediated modulation of dopamine or GABA in the medial prefrontal cortex. The data suggest that alterations in GABAB receptor modulation of medial prefrontal cortical excitatory output may play an important role in the development of sensitization to cocaine.

Effects of 5-HT 1B receptor ligands microinjected into the accumbal shell or core on the sensitization to cocaine in rats

The present study was designed to find out whether 5-HT 1B receptors located in subareas of the nucleus accumbens played a role in cocaine sensitization in rats, and whether pharmacological activation of these receptors could modify this drug effect. Male Wistar rats implanted bilaterally with cannulae into the accumbens shell or core were microinjected with GR 55562 (an antagonist of 5-HT 1B receptors) or CP 93129 (an agonist of 5-HT 1B receptors). The rats, which were repeatedly (for 5 days) administered with cocaine (10 mg/kg) and then challenged with cocaine (10 mg/kg) after 5-day withdrawal period, showed significantly higher locomotor hyperactivity in comparison with the effect observed in saline-pretreated and cocaine challenged rats. GR 55562 (0.1–10 μg/side), administered for 5 days into the accumbens shell, but not into the core, prior to cocaine dose-dependently attenuated cocaine sensitization. When injected for 5 days into either the accumbens shell or core before cocaine, CP 93129 (0.1–10 μg/side) had no effect on the development of cocaine sensitization. To examine the effects of GR 55562 and CP 93129 on the expression of cocaine sensitization, the drugs were given acutely before a challenge dose of cocaine (10 mg/kg) on day 10. No change in cocaine sensitization was observed after injection of GR 55562 (0.1–10 μg/side) to the either accumbens subregion or after injection of CP 93129 (0.1–10 μg/side) into the core. However, an intra-accumbens shell injection of CP 93129 (10–30 μg/side) increased sensitization to cocaine, and this enhancement was attenuated after local injection of GR 55562 (1 μg/side). Our findings indicate that behavioral sensitization to cocaine may be modulated by 5-HT 1B receptor ligands in the accumbens shell, but not into the core. They suggest that the inhibition of 5-HT 1B receptors in the accumbens shell attenuates the development, whereas their pharmacological activation enhances the expression of cocaine sensitization.

Preexposure to, but not cotreatment with, the neurotensin antagonist SR 48692 delays the development of cocaine sensitization.

This study examined the role of neurotensin (NT) in the development of cocaine sensitization using the novel nonpeptide NT antagonist SR 48692. Male Sprague-Dawley rats received five daily administrations of SR 48692 (80 micrograms/kg, IP or PO) or vehicle. Following a 7 day drug-free period, cocaine-induced (15 mg/kg, IP) locomotor activity was assessed. Subsequent cocaine tests occurred every other day. No differences were observed between groups during the first day of cocaine testing. Sensitization to the locomotor activating effects of cocaine occurred rapidly in the controls reaching peak effects by the third cocaine challenge injection. By contrast, subjects preexposed to SR 48692 IP were delayed in the development of cocaine sensitization maintaining significantly lower cocaine-induced activity counts relative to controls until the sixth cocaine challenge injection. Preexposure to SR 48692 PO also produced an attenuating effect on the development of cocaine sensitization. The decreased cocaine-induced activity in SR 48692-preexposed subjects did not appear to be the result of a locomotor deficit as SR 48692-preexposed subjects exhibited increased activity rates following a high dose (30 mg/kg, IP) cocaine challenge injection. In an additional experiment, the effect of cotreatment with SR 48692 on the development of cocaine sensitization was assessed. Subjects were cotreated with SR 48692 (80 micrograms/kg, IP) or vehicle 60 minutes prior to each of two cocaine (15 mg/kg, IP) or saline preexposure injections. Following a drug-free day, subjects were tested for cocaine-induced (15 mg/kg, IP) locomotor activation. SR 48692 cotreatment had no effect on the development of sensitization to cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)