Cocaine Self-administration Experience Research Articles

Astrocyte Ca2+ in the dorsal striatum suppresses neuronal activity to oppose cue-induced reinstatement of cocaine seeking.

Recent literature supports a prominent role for astrocytes in regulation of drug-seeking behaviors. The dorsal striatum, specifically, is known to play a role in reward processing with neuronal activity that can be influenced by astrocyte Ca2+. However, the manner in which Ca2+ in dorsal striatum astrocytes impacts neuronal signaling after exposure to self-administered cocaine remains unclear. We addressed this question following over-expression of the Ca2+ extrusion pump, hPMCA2w/b, in dorsal striatum astrocytes and the Ca2+ indicator, GCaMP6f, in dorsal striatum neurons of rats that were trained to self-administer cocaine. Following extinction of cocaine-seeking behavior, the rats over-expressing hMPCA2w/b showed a significant increase in cue-induced reinstatement of cocaine seeking. Suppression of astrocyte Ca2+ increased the amplitude of neuronal Ca2+ transients in brain slices, but only after cocaine self-administration. This was accompanied by decreased duration of neuronal Ca2+ events in the cocaine group and no changes in Ca2+ event frequency. Acute administration of cocaine to brain slices decreased amplitude of neuronal Ca2+ in both the control and cocaine self-administration groups regardless of hPMCA2w/b expression. These results indicated that astrocyte Ca2+ control over neuronal Ca2+ transients was enhanced by cocaine self-administration experience, although sensitivity to acutely applied cocaine remained comparable across all groups. To explore this further, we found that neither the hMPCA2w/b expression nor the cocaine self-administration experience altered regulation of neuronal Ca2+ events by NPS-2143, a Ca2+ sensing receptor (CaSR) antagonist, suggesting that plasticity of neuronal signaling after hPMCA2w/b over-expression was unlikely to result from elevated extracellular Ca2+. We conclude that astrocyte Ca2+ in the dorsal striatum impacts neurons via cell-intrinsic mechanisms (e.g., gliotransmission, metabolic coupling, etc.) and impacts long-term neuronal plasticity after cocaine self-administration differently from neuronal response to acute cocaine. Overall, astrocyte Ca2+ influences neuronal output in the dorsal striatum to promote resistance to cue-induced reinstatement of cocaine seeking.

The transition to cocaine addiction: the importance of pharmacokinetics for preclinical models.

A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies, this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people, bouts of use are thought to be more intermittent. Here, we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out, the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.

Sex differences in incentive-sensitization produced by intermittent access cocaine self-administration

Intermittent Access (IntA) cocaine self-administration, which models intermittent patterns of cocaine use in humans during the transition to addiction, is especially effective in producing incentive-sensitization and other addiction-like behavior in male rats. However, female rats show more robust psychomotor sensitization than males, and following initial use, women develop problematic patterns of drug use more readily than men. We hypothesized, therefore, that female rats might be more susceptible to the incentive-sensitization produced by IntA experience. To assess changes in motivation for cocaine, using a behavioral economic indicator of cocaine demand ("elasticity" of demand curves), and other addiction-like behavior, as a function of IntA cocaine self-administration experience in male and female rats. IntA experience produced a progressive increase in motivation for cocaine in both males and females, as indicated by a decrease in the elasticity of cocaine demand curves, and this persisted undiminished following 14days of abstinence. However, IntA produced a more rapid and greater increase in motivation for cocaine (incentive-sensitization) in females than males. Females also consumed more cocaine than males, although this did not predict changes in motivation. On the other hand, there were no sex differences in the preferred level of cocaine consumption when cost was low (Q0), nor in cocaine- or cue-induced reinstatement of drug-seeking behavior. The observation that females are more susceptible to incentive-sensitization when intermittently exposed to cocaine may provide a mechanism for the more rapid development of problematic drug use in females ("telescoping effect") reported in clinical studies.

A neuronal activation correlate in striatum and prefrontal cortex of prolonged cocaine intake

Maladaptive changes in the involvement of striatal and frontal cortical regions in drug use are thought to underlie the progression to habitual drug use and loss of cognitive control over drug intake that occur with accumulating drug experience. The present experiments focus on changes in neuronal activity in these regions associated with short-term (10 days) and long-term (60 days) self-administration of cocaine. Quantitative in situ hybridization for the immediate early gene Mkp1 was combined with statistical parametric mapping to assess the distribution of neuronal activity. We hypothesized that neuronal activity in striatum would increase in its dorsal part and that activity in frontal cortex would decrease with prolonged cocaine self-administration experience. Expression of Mkp1 was profoundly increased after cocaine self-administration, and the magnitude of this effect was greater after short-term compared to long-term self-administration. Increased neuronal activity was seen in both dorsal and ventral sectors of the striatum after 10 days exposure to cocaine. However, enhanced activity was restricted to dorsomedial and dorsocentral striatum after 60 days cocaine self-administration. In virtually all medial prefrontal and most orbitofrontal areas, increased expression of Mkp1 was observed after 10 days of cocaine taking, whereas after 60 days, enhanced expression was restricted to caudal parts of medial prefrontal and caudomedial parts of orbitofrontal cortex. Our data reveal functional changes in cellular activity in striatum and frontal cortex with increasing cocaine self-administration experience. These changes might reflect the neural processes that underlie the descent from recreational drug taking to compulsive cocaine use.

Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats.

Relapsing to drug abuse despite periods of abstinence and sincere attempts to quit is one of the most pernicious facets of addiction. Unfortunately, little is known about how the dopamine (DA) system functions after periods of drug abstinence, particularly its role in behavior in nondrug situations. Here, rats learned about food-paired stimuli after prolonged abstinence from cocaine self-administration. Using voltammetry, we found that real-time DA signals in cocaine-experienced rats were strikingly altered relative to controls. Further, cocaine-experienced animals found reward-predictive stimuli abnormally salient and spent more time interacting with cues. Therefore, cocaine induces neuroplastic changes in the DA system that biases animals toward salient stimuli (including reward-associated cues), putting addicts at increasing risk to relapse as addiction increases in severity.

Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

Cocaine Self-Administration Experience Induces Pathological Phasic Accumbens Dopamine Signals and Abnormal Incentive Behaviors in Drug-Abstinent Rats

A therapeutic combination of metyrapone and oxazepam increases brain levels of GABA-active neurosteroids and decreases cocaine self-administration in male rats

In rodents, the behavioral and neurochemical effects resulting from the pharmacological blockade of the hypothalamo–pituitary–adrenal (HPA) axis are unclear. Metyrapone, a corticosterone synthesis inhibitor, has been demonstrated to reduce cocaine-related behaviors, especially in a low-dose combination with oxazepam, a benzodiazepine. Although this combination therapy (MET/OX) also reduces drug-taking and drug-seeking behaviors in both rodents and cocaine-dependent humans, these effects are not correlated with plasma glucocorticoid levels. In this brief report, we present data demonstrating that this MET/OX combination enhances brain levels of the GABA-active steroid metabolites, tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone. Male rats, trained to self-administer cocaine or that received yoked-saline infusions, were pretreated with MET/OX, at doses that reduced cocaine-motivated responding, or vehicle. Allopregnanolone and THDOC were measured using liquid chromatography–mass spectroscopy (LC–MS/MS) in the prefrontal cortex and amygdala in the brains from these rats. THDOC levels were enhanced following MET/OX pretreatment in both brain regions, regardless of cocaine self-administration experience. However, allopregnanolone was selectively enhanced in the rats that self-administered cocaine, but not in rats in the yoked-saline group. Thus, the MET/OX combination increased neurosteroid content in brain regions important for drug addiction. These neurosteroids have been shown to reduce cocaine-related behaviors and may contribute to the behavioral effects of MET/OX combination therapy.

Pharmacology of Self‐Administration of a Non‐Selective Sigma1/2 Receptor Agonist, 1,3‐di‐o‐tolylguanidine (DTG), and its Induction of Sigma1‐Mediated Reinforcement in Rats

Previous studies showed that sigma1 receptor (σ1R) agonists (e.g. PRE‐084, (+)‐pentazocine) were reinforcing in rats with cocaine or d‐methamphetamine self‐administration (SA) experience, but not in experimentally naïve rats. Further studies demonstrated that the induction of σ1R agonist SA specifically occurred with SA of drugs acting at the dopamine transporter (DAT) but not with other abused drugs (e.g. heroin, ketamine). In contrast to effects with selective σ1R agonists, a recent study showed reinforcing effects of the non‐selective σ1/2R agonist DTG (1.0 mg/kg/inj) in naïve rats. The present study assessed the pharmacology of DTG SA, and whether experience with its SA would induce SA of a selective σ1R agonist, PRE‐084. Responding of rats trained with SA of DTG (0.1‐3.2 mg/kg/inj) under an FR 5‐response schedule of reinforcement was insensitive to antagonism by dopamine (DA) receptor antagonists (SCH 39166, L‐741626) which dose‐dependently right‐shifted cocaine (0.03‐1.0 mg/kg/inj) SA dose‐effect curves in a separate group of rats trained with SA of cocaine. Further, σR antagonists (haloperidol, BD 1063) blocked SA of DTG, but of these only haloperidol, which is also a DA antagonist, blocked cocaine SA. Pretreatments with PRE‐084 and the DAT inhibitor WIN 35,428 dose‐dependently left‐shifted dose‐effect curves for DTG and cocaine SA. The present results suggest that DA‐uptake inhibition while sufficient is not necessary for induction of reinforcement by σ1R agonists, and that once induced σR‐mediated reinforcement is independent of traditional DA receptor mechanisms.

Performance on a strategy set shifting task in rats following adult or adolescent cocaine exposure.

Neuropsychological testing is widespread in adult cocaine abusers, but lacking in teens. Animal models may provide insight into age-related neuropsychological consequences of cocaine exposure. The objective of the present study is to determine whether developmental plasticity protects or hinders behavioral flexibility after cocaine exposure in adolescent vs. adult rats. Using a yoked-triad design, one rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling cocaine delivery (1.0mg/kg) self-administered for 18 sessions (starting P37 or P77), followed by 18 drug-free days. Rats next were tested in a strategy set shifting task, lasting 11-13 sessions. Cocaine self-administration did not differ between age groups. During initial set formation, adolescent-onset groups required more trials to reach criterion and made more errors than adult-onset groups. During the set shift phase, rats with adult-onset cocaine self-administration experience had higher proportions of correct trials and fewer perseverative + regressive errors than age-matched yoked-controls or rats with adolescent-onset cocaine self-administration experience. During reversal learning, rats with adult-onset cocaine experience (self-administered or passive) required fewer trials to reach criterion, and the self-administering rats made fewer perseverative + regressive errors than yoked-saline rats. Rats receiving adolescent-onset yoked-cocaine had more trial omissions and longer lever press reaction times than age-matched rats self-administering cocaine or receiving yoked-saline. Prior cocaine self-administration may impair memory to reduce proactive interference during set shifting and reversal learning in adult-onset but not adolescent-onset rats (developmental plasticity protective). Passive cocaine may disrupt aspects of executive function in adolescent-onset but not adult-onset rats (developmental plasticity hinders).

D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats.

Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.

Self-Administration of Cocaine Induces Dopamine-Independent Self-Administration of Sigma Agonists

Sigma(1) receptors (σ(1)Rs) are intracellularly mobile chaperone proteins implicated in several disease processes, as well as psychiatric disorders and substance abuse. Here we report that although selective σ(1)R agonists (PRE-084, (+)-pentazocine) lacked reinforcing effects in drug-naive rats, over the course of 28 experimental sessions, which was more than sufficient for acquisition of cocaine self-administration, responding was not maintained by either σ(1)R agonist. In contrast, after subjects self-administered cocaine σ(1)R agonists were readily self-administered. The induced reinforcing effects were long lasting; a response for which subjects had no history of reinforcement was newly conditioned with both σ(1)R agonists, extinguished when injections were discontinued, and reconditioned when σ(1)R agonists again followed responses. Experience with food reinforcement was ineffective as an inducer of σ(1)R agonist reinforcement. Although a variety of dopamine receptor antagonists blocked cocaine self-administration, consistent with its dopaminergic mechanism, PRE-084 self-administration was entirely insensitive to these drugs. Conversely, the σR antagonist, BD1063, blocked PRE-084 self-administration but was inactive against cocaine. In microdialysis studies i.v. PRE-084 did not significantly stimulate dopamine at doses that were self-administered in rats either with or without a cocaine self-administration experience. The results indicate that cocaine experience induces reinforcing effects of previously inactive σ(1)R agonists, and that the mechanism underlying these reinforcing effects is dopamine independent. It is further suggested that induced σ(1)R mechanisms may have an essential role in treatment-resistant stimulant abuse, suggesting new approaches for the development of effective medications for stimulant abuse.

Emergence of context-associated GluR1 and ERK phosphorylation in the nucleus accumbens core during withdrawal from cocaine self-administration

Reexposure to cocaine-associated environments promotes relapse to cocaine seeking and represents a persistent impediment to successful abstinence. Neurobiological adaptations are thought to underlie the preservation of drug-seeking behavior during protracted withdrawal periods, possibly including changes associated specifically with cocaine-paired contexts. We measured GluR(1) (S845) and extracellular signal-regulated kinase (ERK) phosphorylation in rat striatal subregions in an animal model of cocaine relapse. Animals with cocaine self-administration experience and their yoked partners were exposed to extinction conditions for one hour in the drug-paired environmental context after one day or three weeks withdrawal to measure protein phosphorylation induced by the cocaine-paired context in the absence of cocaine reinforcement. GluR(1) (S845) (an index of protein kinase A (PKA) activity) and ERK phosphorylation increased in the nucleus accumbens core of self-administering but not yoked animals after three weeks (but not one day) withdrawal, indicating a time-dependent emergence of context-associated protein phosphorylation in this accumbens subregion. In comparison, animals trained to self-administer sucrose displayed a similar increase in ERK, but not GluR(1) (S845) , phosphorylation following reexposure to a sucrose-paired environment three weeks later, indicating that GluR(1) (S845) phosphorylation did not result solely from lever press behavior per se. In contrast, basal (home cage) GluR(1) (S845) phosphorylation was elevated in the nucleus accumbens shell and caudate-putamen after one day or three weeks cocaine withdrawal regardless of context exposure. These results suggest that time-dependent emergence of context-associated GluR(1) (S845) phosphorylation in the nucleus accumbens core may contribute to the persistence of cocaine-seeking behavior, whereas ERK phosphorylation may be a consequence of this behavior.

Differences in D2 dopamine receptor availability and reaction to novelty in socially housed male monkeys during abstinence from cocaine

Studies in socially housed monkeys have demonstrated an influence of position in the social dominance hierarchy on brain dopamine D2 receptors and the reinforcing effects of cocaine that dissipates after long-term cocaine self-administration. The aims of the study were to examine the effects of abstinence from cocaine on D2 receptors in socially housed monkeys and to extend behavioral characterizations to measures of reactivity to a novel object. Twelve socially housed male cynomolgus monkeys with extensive cocaine self-administration experience were used (average lifetime intakes ∼270 and 215 mg/kg for dominant and subordinate monkeys, respectively). Abstinence lasted for approximately 8 months, after which D2 receptor availability was assessed using positron emission tomography and the D2 ligand [18F]fluoroclebopride. Reaction to novelty was also assessed in these subjects as well as nine individually housed monkeys. During abstinence, D2 receptor availability in the caudate nucleus was significantly higher in dominant versus subordinate monkeys. Average latency to touch a novel object was also significantly higher in dominant monkeys compared to subordinates or individually housed monkeys. In socially experienced monkeys, a significant positive correlation was observed between caudate nucleus D2 receptor availability and latencies to touch the novel object. Although chronic cocaine self-administration blunts the ability of social dominance to alter D2 receptor availability and sensitivity to the reinforcing effects of cocaine, this influence reemerges during abstinence. In addition, the data suggest that prior experience with social dominance can lead to longer latencies in reaction to novelty--a personality trait associated with low vulnerability to cocaine abuse.

Effects of self-administered cocaine in adolescent and adult male rats on orbitofrontal cortex-related neurocognitive functioning

Deficits in amygdala-related stimulus-reward learning are produced following 18 drug-free days of cocaine self-administration or its passive delivery in rats exposed during adulthood. No deficits in stimulus-reward learning are produced by cocaine exposure initiated during adolescence. To determine if age of initiating cocaine exposure differentially affects behavioral functioning of an additional memory system linked to cocaine addiction, the orbitofrontal cortex. A yoked-triad design (n = 8) was used. One rat controlled cocaine delivery and the other two passively received cocaine or saline. Rats controlling drug delivery (1.0 mg/kg) self-administered cocaine from either P37-P59 or P77-P99, and then underwent 18 drug-free days (P60-P77 vs. P100-P117). Rats next were tested for acquisition of odor-delayed win-shift behavior conducted over 15 sessions (P78-P96 vs. P118-P136). Cocaine self-administration did not differ between adults and adolescents. During the test phase of the odor-delayed win-shift task (relatively difficult task demands), rats from both drug-onset ages showed learning deficits. Rats with cocaine self-administration experience committed more errors and had longer session latencies compared to rats passively receiving saline or cocaine. Rats with adolescent-onset cocaine self-administration experience showed an additional learning deficit by requiring more sessions to reach criterion levels for task acquisition compared to same-aged passive saline controls or rats with adult-onset cocaine self-administration experience. Rats passively receiving cocaine did not differ from the passive saline control from either age group. Rats with adolescent-onset cocaine self-administration experience were more impaired in an orbitofrontal cortex-related learning task than rats with adult-onset cocaine self-administration experience.

Cocaine self-administration produces a persistent increase in dopamine D2 High receptors

Cocaine addicts are reported to have decreased numbers of striatal dopamine D2 receptors. However, in rodents, repeated cocaine administration consistently produces hypersensitivity to the psychomotor activating effects of both indirect dopamine agonists, such as cocaine itself, and importantly, to direct-acting D2 receptor agonists. The current study reports a possible resolution to this long-standing paradox. The dopamine D2 receptor exists in both a low and a high-affinity state, and dopamine exerts its effects via the more functionally relevant high-affinity D2 receptor (D2 High). We report here that cocaine self-administration experience produces a large (approximately 150%) increase in the proportion of D2 High receptors in the striatum with no change in the total number of D2 receptors, and this effect is evident both 3 and 30 days after the discontinuation of cocaine self-administration. Changes in D2 High receptors would not be evident with the probes used in human (and non-human primate) imaging studies. We suggest, therefore, that cocaine addicts and animals previously treated with cocaine may be hyper-responsive to dopaminergic drugs in part because an increase in D2 High receptors results in dopamine supersensitivity. This may also help explain why stimuli that increase dopamine neurotransmission, including drugs themselves, are so effective in producing relapse in individuals with a history of exposure to cocaine.

The Dorsal Subiculum Mediates the Acquisition of Conditioned Reinstatement of Cocaine-Seeking

Contextual stimuli present during a single lifetime cocaine self-administration experience acquire occasion-setting actions sufficient to persistently elicit cocaine-seeking behavior in rats, with effects lasting nearly 1 year. The goal of this study was to identify neural substrates mediating the acquisition of drug-related conditioning taking place during a single cocaine self-administration experience with focus on the subicular formation, a brain site that has been implicated in associative learning relevant for conditioned reward-seeking including conditioned reinstatement. Male Wistar rats were given 2 h of response-contingent access to intravenous cocaine or saline in the presence of distinct stimuli that served as contextual stimuli associated with the availability and subjective effects of cocaine (S(+)) vs saline (S(-)). Before onset of the sessions, rats received bilateral microinjections of tetrodotoxin (TTX) into the ventral subiculum (VSUB) or dorsal subiculum (DSUB). Following extinction of responding by withholding cocaine, rats were subjected to reinstatement tests in which exposure to the cocaine- (but not saline) associated stimulus produced strong recovery of responding. This effect was completely abolished in rats with transient TTX inactivation of the DSUB during the conditioning session. TTX inactivation of the VSUB during conditioning did not alter the response-reinstating effects of the cocaine cue. The results suggest that functional integrity of the DSUB, but not VSUB, is critical for the acquisition of conditioned cocaine-seeking controlled by contextual stimuli under conditions where such learning occurs during a single conditioning trial.

Drug seeking becomes compulsive after prolonged cocaine self-administration.

Compulsive drug use in the face of adverse consequences is a hallmark feature of addiction, yet there is little preclinical evidence demonstrating the actual progression from casual to compulsive drug use. Presentation of an aversive conditioned stimulus suppressed drug seeking in rats with limited cocaine self-administration experience, but no longer did so after an extended cocaine-taking history. In contrast, after equivalent extended sucrose experience, sucrose seeking was still suppressed by an aversive conditioned stimulus. Persistent cocaine seeking in the presence of signals of environmental adversity after a prolonged cocaine-taking history was not due to impaired fear conditioning, nor to an increase in the incentive value of cocaine, and may reflect the establishment of compulsive behavior.

Behavioural sensitization and enhanced dopamine response in the nucleus accumbens after intravenous cocaine self-administration in mice.

The behavioural effects of cocaine are enhanced in animals with a prior history of repeated cocaine administration. This phenomenon, referred to as sensitization, is also associated with an increase in cocaine-evoked extracellular dopamine levels in the nucleus accumbens. Behavioural and neurochemical sensitization has been demonstrated in rats with a prior history of cocaine self-administration and in those that had received experimenter-administered cocaine. Although it is clear that the repeated non-contingent administration also results in behavioural sensitization in the mouse, the issue of whether behavioural and neurochemical sensitization also occur in this species following intravenous cocaine self-administration has not been assessed. The present study used the technique of in vivo microdialysis in conjunction with operant self-administration to characterize cocaine-evoked locomotor activity and dopamine levels in the nucleus accumbens in mice with a prior history of intravenous cocaine self-administration or those that had received yoked infusions of cocaine. Mice that had received contingent or non-contingent infusions of cocaine exhibited an enhanced behavioural response to cocaine and increased cocaine-evoked dopamine levels in the nucleus accumbens. There was no difference between groups in the magnitude of this effect. Prior exposure to cocaine did not modify baseline dopamine levels in the nucleus accumbens. These data demonstrate that mice with previous cocaine self-administration experience show an enhanced behavioural and dopamine response to cocaine in the nucleus accumbens. Furthermore, control over cocaine infusion does not significantly alter the magnitude of the sensitized behavioural and presynaptic dopamine responses observed in response to a challenge dose of cocaine.

Intravenous ethanol/cocaine self-administration initiates high intake of intravenous ethanol alone

Evidence suggests that ethanol (EtOH) preexposure influences the rewarding valence of subsequent EtOH use. This study was conducted to determine if EtOH preexposure through EtOH/cocaine self-administration facilitates the motivational effects of EtOH alone. Rats self-administered intravenous (iv) EtOH/cocaine combinations (EtOH/Cocaine Fading group; EtOH 125.0 mg/kg/inj+Cocaine 0.1–0.75 mg/kg/inj) during a preexposure period. Consequently, these rats self-administered intravenous EtOH alone (62.5, 125.0, 250.0 and 500.0 mg/kg/inj) significantly more than a control group with prior cocaine self-administration experience (0.1–0.75 mg/kg/inj). In addition, at equal EtOH intake levels, locomotor activity was significantly enhanced in the EtOH/Cocaine Fading group but not the Cocaine Control animals ( P=.01). The amount of EtOH self-administered in the EtOH/Cocaine Fading group during 1-h sessions (≈0.5–2.0 g/kg) corresponded with blood alcohol levels (BAL) ranging from 44 to 221 mg/dl. The highest BALs reported here have not previously been demonstrated after voluntary EtOH intake through any route of administration. These data suggest that preexposure to EtOH during EtOH/cocaine self-administration sessions modified neural substrates underlying both the reinforcing and locomotor responses to EtOH alone. Further studies utilizing intravenous EtOH self-administration will allow identification of various long-term behavioral and neural consequences of voluntary high EtOH intake.

Progression of Changes in Dopamine Transporter Binding Site Density as a Result of Cocaine Self-Administration in Rhesus Monkeys

The present study examined the time course of alterations in levels of dopamine transporter (DAT) binding sites that accompany cocaine self-administration using quantitative in vitro receptor autoradiography with [(3)H]WIN 35,428. The density of dopamine transporter binding sites in the striatum of rhesus monkeys with 5 d, 3.3 months, or 1.5 years of cocaine self-administration experience was compared with DAT levels in cocaine-naive control monkeys. Animals in the long-term (1.5 years) exposure group self-administered cocaine at 0.03 mg/kg per injection, whereas the initial (5 d) and chronic (3.3 months) treatment groups were each divided into lower dose (0.03 mg/kg per injection) and higher dose (0.3 mg/kg per injection) groups. Initial cocaine exposure led to moderate decreases in [(3)H]WIN 35,428 binding sites, with significant changes in the dorsolateral caudate (-25%) and central putamen (-19%) at the lower dose. Longer exposure, in contrast, resulted in elevated levels of striatal binding sites. The increases were most pronounced in the ventral striatum at the level of the nucleus accumbens shell. At the lower dose of the chronic phase, for example, significant increases of 21-42% were measured at the caudal level of the ventral caudate, ventral putamen, olfactory tubercle, and accumbens core and shell. Systematic variation of cocaine dose and drug exposure time demonstrated the importance of these factors in determining the intensity of increased DAT levels. With self-administration of higher doses especially, increases were more intense and included dorsal portions of the striatum so that every region at the caudal level exhibited a significant increase in DAT binding sites (20-54%). The similarity of these findings to previous studies in human cocaine addicts strongly suggest that the increased density of dopamine transporters observed in studies of human drug abusers are the result of the neurobiological effects of cocaine, ruling out confounds such as polydrug abuse, preexisting differences in DAT levels, or comorbid psychiatric conditions.