Barbara A. Sorg

A role for sensitization in craving and relapse in cocaine addiction.

Sensitization to cocaine refers to the behavioral model of cocaine addiction where the motor stimulant effect of cocaine is augmented for months after discontinuing a regimen of repeated cocaine injections. There has been speculation that the neuroadaptations mediating this sensitization phenomenon may, in part, underlie the behavioral changes produced by chronic cocaine abuse, including paranoia, craving and relapse. Criteria are proposed that may assist in determining which neuroadaptations are most relevant in this regard. Using these criteria, a model is presented that endeavors to incorporate neuroadaptations issuing directly from the pharmacological effects of cocaine and those arising from learned associations the organism makes with the cocaine injection procedure and pharmacological actions. It is proposed that the pharmacological neuroadaptations predominate in the manifestation of cocaine-induced paranoia, while the changes derived from learning may provide more critical underpinnings for cocaine craving and relapse.

Effects of cocaine and footshock stress on extracellular dopamine levels in the ventral striatum

Behavioral and neurochemical cross-sensitization between cocaine and stress was examined. The effects of stress and cocaine on extracellular levels of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were measured by in vivo microdialysis in the rostral ventral striatum, including the nucleus accumbens. Pretreatment with a daily 20 min footshock stress (0.45 mA/200 ms/s) for 5 days enhanced the cocaine-induced increase in extracellular dopamine levels in shock compared to sham shock-pretreated rats. The motor stimulant response to acute cocaine was also augmented in shock-pretreated rats. There was a slight but significant decrease in the levels of DOPAC and HVA in both groups following cocaine but no differences between shock and sham shock animals. In contrast, in the converse experiment, pretreatment with daily cocaine (15 mg/kg, i.p.) for 5 days did not significantly alter the stress-induced levels of extracellular dopamine compared to controls. The levels of DOPAC and HVA were not different between cocaine- and saline-pretreated groups although there was a trend towards enhanced metabolite levels in cocaine-pretreated animals. These data in part support a role for enhanced dopamine neutrotransmission in mediating behavioral cross-sensitization between psychostimulants and stress.

In Vivo Cocaine Experience Generates Silent Synapses

Studies over the past decade have enunciated silent synapses as prominent cellular substrates for synaptic plasticity in the developing brain. However, little is known about whether silent synapses can be generated postdevelopmentally. Here, we demonstrate that highly salient in vivo experience, such as exposure to cocaine, generates silent synapses in the nucleus accumbens (NAc) shell, a key brain region mediating addiction-related learning and memory. Furthermore, this cocaine-induced generation of silent synapses is mediated by membrane insertions of new, NR2B-containing N-methyl-D-aspartic acid receptors (NMDARs). These results provide evidence that silent synapses can be generated de novo by in vivo experience and thus may act as highly efficient neural substrates for the subsequent experience-dependent synaptic plasticity underlying extremely long-lasting memory.

Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex

The interaction between cocaine and footshock stress was evaluated by determining changes in extracellular dopamine and metabolite levels by in vivo microdialysis in the medial prefrontal cortex. In the first experiment, rats were given one of three treatments: no pretreatment (naive); or five daily injections of cocaine (15 mg/kg, i.p.); or daily saline. Six to seven days later, animals had a microdialysis probe implanted into the medial prefrontal cortex and an acute 20-min footshock stress (0.45 mA/200 ms per s) or sham shock was delivered. The results showed that acute footshock in daily saline pretreated rats increased medial prefrontal cortex extracellular dopamine concentrations to 203% of baseline levels. In rats pretreated with daily cocaine, this stress-induced response was completely abolished and extracellular dopamine was reduced 38% below baseline levels by 100 min post-shock. Naive animals showed a response to footshock that was intermediate between cocaine and saline pretreated rats (156% of baseline). In the second experiment, rats were given either no pretreatment (naive) or five daily 20-min footshock treatments (as above) or daily sham shock. Six to seven days later, an acute cocaine or saline injection was given. In daily sham-pretreated rats, extracellular dopamine levels were increased to 500% of baseline in response to acute cocaine. Pretreatment with daily footshock significantly reduced the response to acute cocaine (216% of baseline). Naive rats showed an intermediate increase that was not significantly different from footshock-pretreated animals (265% of baseline). Locomotor activity measured concurrently with dialysis showed a non-significant trend towards enhanced activity in daily footshock animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Manipulation of dopamine d1-like receptor activation in the rat medial prefrontal cortex alters stress- and cocaine-induced reinstatement of conditioned place preference behavior.

These studies examined the ability of the dopamine D1-like agonist SKF 81297 and D1-like antagonist SCH 23390 in the medial prefrontal cortex to alter the reinstatement of cocaine-induced conditioned place preference behavior. Male Sprague-Dawley rats were fitted with bilateral cannulae over the medial prefrontal cortex and subsequently trained in a conditioned place preference task. Animals were trained in this task using four pairings of cocaine (12 mg/kg, i.p.). Conditioned place preference was demonstrated in all animals, and this behavior was then extinguished over a 5-10-day period before testing for reinstatement. Just prior to reinstatement by immobilization stress or a cocaine priming injection (5 mg/kg, i.p.), a microinjection of the D1-like receptor antagonist SCH 23390 (0.01, 0.1 or 1.0 microg/side), or the D1-like receptor agonist SKF 81297 (0.1, 0.3 or 1.0 microg/side) was given into the medial prefrontal cortex. SCH 23390 blocked both stress- and cocaine-induced reinstatement of conditioned place preference after the two higher doses were administered into the medial prefrontal cortex. The highest dose of SKF 81297 (1.0 microg/side) prevented immobilization stress- but not cocaine-induced reinstatement. The highest dose of these drugs given in the absence of stress or cocaine did not produce reinstatement. The results indicate that immobilization stress given within the place-preference chamber is capable of producing reinstatement of cocaine-seeking behavior. The microinjection studies suggest that D1-like receptor antagonism within the prefrontal cortex is sufficient to block reinstatement by stress and cocaine. Furthermore, the results from D1-like receptor activation in the medial prefrontal cortex point to utilization of different neural pathways for stress- and cocaine-induced reinstatement.

A Silent Synapse-Based Mechanism for Cocaine-Induced Locomotor Sensitization

Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

The effect of trait anxiety and situational stress on working memory capacity

Abstract Individuals were divided into high and low trait anxiety groups and were exposed to 10 min of a stressful environment (a video game competition) or a nonstressful environment. Their subsequent performance on word span and reading span tasks was examined. Unlike the word span task, which measures short-term storage capacity, the reading span task measures storage and manipulation capacity. No differences between groups were found on word span performance. In contrast, there were interactive effects of trait anxiety and situational stress on reading span performance. The performance of the high anxiety subjects decreased in the stressful condition. However, the high anxiety subjects performed better than the low anxiety subjects in the nonstressful condition. These data provide direct evidence for changes in working memory capacity resulting from the joint effects of trait anxiety and situational stress.

Diurnal differences in dopamine transporter and tyrosine hydroxylase levels in rat brain: dependence on the suprachiasmatic nucleus.

Time of day can influence cocaine-seeking behavior in rats, and this influence may depend on the suprachiasmatic nucleus (SCN). We used western blots to measure expression of dopamine transporter (DAT) and tyrosine hydroxylase (TH) proteins in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and caudate in sham and SCN-lesioned (SCNx) rats at ZT4 (Zeitgeber time 4, 4 h after lights-on) or ZT20 (8 h after lights-off). In the mPFC, DAT levels were lower at ZT20 than at ZT4 in sham but not SCNx rats. In the NAc, DAT expression was higher at ZT20 than at ZT4, and this effect was blunted in SCNx rats. Caudate DAT levels were unaffected by time of day or SCNx. Levels of TH did not change in mPFC with time of day or SCN lesion; TH levels were higher at ZT20 in the NAc, with a trend towards higher levels at this time in SCNx rats. Caudate TH expression was slightly elevated at ZT20 in sham but not in SCNx rats. We conclude that DAT and TH within these brain regions exhibit diurnal variation and dependence on the SCN. The results may have implications for new strategies to maximize pharmacological treatments for drug addiction.

The NMDA Antagonist MK-801 Disrupts Reconsolidation of a Cocaine-Associated Memory for Conditioned Place Preference but Not for Self-Administration in Rats.

Recent research suggests that drug-related memories are reactivated after exposure to environmental cues and may undergo reconsolidation, a process that can strengthen memories. Conversely, reconsolidation may be disrupted by certain pharmacological agents such that the drug-associated memory is weakened. Several studies have demonstrated disruption of memory reconsolidation using a drug-induced conditioned place preference (CPP) task, but no studies have explored whether cocaine-associated memories can be similarly disrupted in cocaine self-administering animals after a cocaine priming injection, which powerfully reinstates drug-seeking behavior. Here we used cocaine-induced CPP and cocaine self-administration to investigate whether the N-methyl-D-aspartate receptor antagonist (+)-5methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) given just prior to reactivation sessions would suppress subsequent cocaine-primed reinstatement (disruption of reconsolidation). Systemic injection of MK-801 (0.05 or 0.20 mg/kg administered intraperitoneally) in rats just prior to reactivation of the cocaine-associated memory in the CPP context attenuated subsequent cocaine-primed reinstatement, while no disruption occurred in rats that did not receive reactivation in the CPP context. However, in rats trained to self-administer cocaine, systemic administration of MK-801 just prior to either of two different types of reactivation sessions had no effect on subsequent cocaine-primed reinstatement of lever-pressing behavior. Thus, systemic administration of MK-801 disrupted the reconsolidation of a cocaine-associated memory for CPP but not for self-administration. These findings suggest that cocaine-CPP and self-administration do not use similar neurochemical processes to disrupt reconsolidation or that cocaine-associated memories in self-administering rats do not undergo reconsolidation, as assessed by lever-pressing behavior under cocaine reinstatement conditions.

Exposure to Cocaine Dynamically Regulates the Intrinsic Membrane Excitability of Nucleus Accumbens Neurons

Drug-induced malfunction of nucleus accumbens (NAc) neurons underlies a key pathophysiology of drug addiction. Drug-induced changes in intrinsic membrane excitability of NAc neurons are thought to be critical for producing behavioral alterations. Previous studies demonstrate that, after short-term (2 d) or long-term (21 d) withdrawal from noncontingent cocaine injection, the intrinsic membrane excitability of NAc shell (NAcSh) neurons is decreased, and decreased membrane excitability of NAcSh neurons increases the acute locomotor response to cocaine. However, animals exhibit distinct cellular and behavioral alterations at different stages of cocaine exposure, suggesting that the decreased membrane excitability of NAc neurons may not be a persistent change. Here, we demonstrate that the membrane excitability of NAcSh neurons is differentially regulated depending on whether cocaine is administered contingently or noncontingently. Specifically, the membrane excitability of NAcSh medium spiny neurons (MSNs) was decreased at 2 d after withdrawal from either 5 d intraperitoneal injections (15 mg/kg) or cocaine self-administration (SA). At 21 d of withdrawal, the membrane excitability of NAcSh MSNs, which remained low in intraperitoneally pretreated rats, returned to a normal level in SA-pretreated rats. Furthermore, after a reexposure to cocaine after long-term withdrawal, the membrane excitability of NAcSh MSNs instantly returned to a normal level in intraperitoneally pretreated rats. Conversely, in SA-pretreated rats, the reexposure elevated the membrane excitability of NAcSh MSMs beyond the normal level. These results suggest that the dynamic alterations in membrane excitability of NAcSh MSNs, together with the dynamic changes in synaptic input, contribute differentially to the behavioral consequences of contingent and noncontingent cocaine administration.