Dose-dependent effect of ethanol on extracellular dopamine in mesolimbic striatum of awake rhesus monkeys: comparison with cocaine across individuals

Abstract Rationale. Dependence on both alcohol and cocaine is a widespread example of polydrug abuse/dependence. It has been hypothesized that ethanol reward is mediated via increased dopaminergic neurotransmission in mesolimbic striatum, as is the case for cocaine. However, little is known about the neurobiology of ethanol in primates, or how the effects of ethanol compare to those of cocaine across individual animals. Objectives. To determine in animals with a history of cocaine exposure whether there is a dopaminergic impact of ethanol in non-human primates, and if so, whether the magnitude of that effect correlates with the dopaminergic effect of cocaine across individuals. Methods. Microdialysis studies were conducted in rhesus monkeys previously trained to self-administer cocaine. The dopaminergic impact of cocaine had been determined in those animals during cocaine self-administration sessions. Probes were placed in the ventral mesolimbic and associational central striatum. Ethanol was administered non-contingently by a slow intravenous infusion at doses of 0.5 g/kg (administered over 10 min) and 1.0 g/kg (administered over 20 min). Results. The mean dopaminergic response to ethanol in four animals (with 2–4 trials in each animal at each dose) indicated a small but significant increase in extracellular dopamine at each dose (12% above baseline at 0.5 g/kg, 22% above baseline at 1.0 g/kg). Examining the responses across individual animals indicated substantial variability, in that two of the four animals showed no increase at either dose. Across individuals, regression analysis of cocaine-induced changes in dopamine with 1.0 g/kg ethanol-induced changes indicated a positive correlation between the drug effects, with a trend in this direction observed with the 0.5-g/kg dose of ethanol. Conclusions. These results provide support for the ability of ethanol to elevate extracellular dopamine in the mesolimbic striatum, though with a modest effect size and variability among individuals. Further, they suggest that some common mechanism influences the effects of ethanol and cocaine on dopaminergic output despite seemingly unrelated pharmacological mechanisms of action. Electronic Publication     

Reciprocal effects of response contingent and noncontingent intravenous heroin on in vivo nucleus accumbens shell versus core dopamine in the rat: a repeated sampling microdialysis study

Rationale Although passive administration of heroin to drug-naive rats increases extracellular dopamine (DA) in the nucleus accumbens (NAc), its ability to do so also after active drug exposure (self-administration) is debated. Objectives This study investigated by repeated microdialysis sampling the inter- and intrasession changes in the responsiveness of the NAc shell and core DA and the behavioral effects of active and passive heroin exposure in the intravenous self-administration/yoked paradigm. Materials and methods Rats were implanted with jugular catheters and bilateral intracerebral chronic guide cannulae. Nose poking in the active hole by master rats resulted in heroin administration to the same subjects and to their yoked mates. Concentric microdialysis probes were inserted daily in the guide cannulae, and changes in dialysate DA in response to heroin exposure (0.05 mg/kg) were monitored in the same subject for 90 min for 4 weeks. Behavior associated with heroin exposure, distinguished into nonstereotyped and stereotyped, was also recorded. Results Dialysate DA increased preferentially in the shell of master rats from the first session (+112%) and throughout the 4 weeks of self-administration (+130–140%). In yoked rats, a preferential but lesser increase in DA in the shell was observed only on the first session (+60%), as the DA response in the NAc core increased progressively (+25–118%), so that within a week, the shell/core ratio was reversed, and this pattern was maintained for the following 2 weeks. Yoked rats showed a progressive and larger increase in stereotyped behaviors than master rats. Conclusions Chronic heroin self-administration increases extracellular DA preferentially in the NAc shell. Response-noncontingent heroin administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.     

Differential neurochemical and behavioral adaptation to cocaine after response contingent and noncontingent exposure in the rat

Rationale In naive rats, passive administration of drugs of abuse preferentially increases extracellular dopamine (DA) in the nucleus accumbens (NAc) shell as compared to the core. Repeated exposure to the same drugs results in behavioral and biochemical sensitization characterized by stereotyped activity and reduction of the shell/core DA response ratio. Objectives The aim of this work is to study the neurochemical and behavioral effects of response-contingent vs response-noncontingent drug administration in rats, who were bilaterally implanted with chronic intracerebral guide cannulae and trained to self-administer cocaine by nose poking in daily 1-h sessions for 3 weeks (5 days/week). Nose poking in the active hole by master rats resulted in intravenous injection of cocaine (0.25 mg/kg) in master rats and in rats yoked to them. Dialysate DA was monitored before, during, and for 30 min after cocaine availability on alternate days by inserting the probe into the NAc shell and core. Stereotyped and non-stereotyped behavior was recorded during the sessions. Results In master rats, dialysate DA increased preferentially in the NAc shell during cocaine self-administration throughout the 3 weeks of cocaine exposure. In yoked rats, DA increased preferentially in the shell but to a lesser extent than in master rats. With continued exposure to cocaine, the shell/core ratio of DA changes decreased progressively and, on the third week, was reversed so that DA increased more in the core than in the shell. Yoked rats showed a progressive and faster increase in stereotyped behaviors than master rats. Conclusions Response-noncontingent cocaine administration is particularly prone, compared to response-contingent administration, to induce behavioral and biochemical sensitization.     

Differential cocaine-induced modulation of glutamate and dopamine transporters after contingent and non-contingent administration

Although dopamine and glutamate transmission has been implicated in cocaine dependence, the effects of the extinction of cocaine self-administration on protein transporters in both of these neurotransmitter systems remain unknown. We have used a yoked-box procedure to simultaneously test rats in triads, one rat that actively self-administered cocaine (CONT), while the other two received yoked injections of either cocaine (NON-CONT) or saline (SALINE). The brains in each triad were removed and processed for quantitative autoradiography immediately after the last session of cocaine self-administration (Day 0), or after 1, 5, or 10 days of extinction, and excitatory amino acid transporters (EAATs) and dopamine transporter (DAT) binding was examined. When compared to NON-CONT and SALINE animals, binding of radioligand to EAATs was significantly lower in the hippocampal CA1 field and the cerebellar cortex of CONT rats on Day 0, although it was significantly higher after 1 day of extinction in the infralimbic cortex. No differences in EAAT binding were observed after 5 or 10 days of extinction in any of the brain regions analyzed. In contrast and at all the time points of extinction, binding to DAT was significantly enhanced in CONT animals when compared to SALINE and NON-CONT rats in different forebrain and mesencephalic regions, including the nucleus accumbens, ventral tegmental area or caudate putamen. These results suggest that changes in protein transporter binding after cocaine self-administration and extinction are transient for EAAT while they are more enduring for DAT, and that they depend on the type of access to cocaine.     

Differential changes in mesolimbic dopamine following contingent and non-contingent MDMA self-administration in mice

Rationale  There is evidence demonstrating changes in dopamine (DA) transmission in the nucleus accumbens (NAc) related to contingent versus non-contingent drug administration. Objectives  The aim of this study was to evaluate basal and 3,4-methylenedioxymethamphetamine (MDMA)-stimulated DA levels in the NAc of mice that had previously received contingent and non-contingent infusions of MDMA. Contingent mice were trained to self-administer MDMA (0.125 mg/kg/infusion) in 2-h sessions for 10 days. Yoked mice received either MDMA at the same dose or saline. Forty-eight hours after the last MDMA or saline administration, DA levels were measured by in vivo microdialysis before and after an MDMA (10 mg/kg, i.p.) challenge. Binding of [³H]-mazindol and [³H]-citalopram was evaluated by autoradiography. Results  Animals receiving MDMA infusions showed significantly lower basal DA levels than the yoked saline group. A reduced activation of DA was observed following MDMA in contingent mice with respect to both yoked MDMA and saline mice. No significant alterations in DA transporter or serotonin transporter were observed in the three groups of mice. Conclusions  These results suggest that prolonged exposure to MDMA in mice produces changes in basal DA levels after drug withdrawal and a decreased neurochemical response at the level of the mesolimbic DA reward pathway that is, in part, related to instrumental learning during self-administration.     

Acamprosate blocks the increase in dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus

Recently, we have shown that acamprosate is able to modulate extracellular dopamine (DA) levels in the nucleus accumbens (NAc) and may act as an antagonist of N-methyl-D-aspartate (NMDA) receptors. Neurochemical studies show that chemical stimulation (using NMDA) of the ventral subiculum (vSub) of the hippocampus produces robust and sustained increases in extracellular DA levels in the NAc, an effect mediated through ionotropic glutamate (iGlu) receptors. The present study examines whether acamprosate locally infused in the NAc of rats could block or attenuate the increase in NAc extracellular DA elicited by chemical stimulation (with 5 mM NMDA) of the ventral subiculum of the hippocampus. The stimulation of the vSub during perfusion of artificial cerebrospinal fluid in NAc induced a significant and persistent increase in NAc DA levels. Reverse dialysis of 0.05 mM acamprosate in NAc blocked the increase in DA evoked by the chemical stimulation of the vSub. These data support the possibility that the antagonism at the NMDA receptors in NAc can explain, at least in part, the mechanism of action of this drug.     

Differences in extracellular dopamine concentrations in the nucleus accumbens during response-dependent and response-independent cocaine administration in the rat

 Studies indicate that nucleus accumbens (NAcc) dopamine neurotransmission is involved in the reinforcing and direct effects of cocaine. The present study was initiated to explore further the relationship of NAcc extracellular dopamine concentrations ([DA]_e) and cocaine self-administration using a yoked littermate design. In the first experiment, one rat from each litter was trained to self-administer cocaine IV (SA; 0.33 mg/inf) under a fixed ratio 2 schedule, while a second rat received simultaneous infusions of cocaine yoked to the infusions of the SA (YC). NAcc [DA]_e and cocaine concentrations ([COC]) were assessed during the test sessions using in vivo microdialysis combined with microbore HPLC procedures. [DA]_e and [COC] were significantly elevated in the SA and YC groups during the self-administration session; however, [DA]_e were greater in the SA group compared to the YC group in the first hour of the session, even though [COC] were not significantly different. On the following day, the rats previously allowed to self-administer cocaine were administered response-independent cocaine infusions yoked to the infusion pattern from the previous day. [DA]_e were significantly elevated above baseline levels during the session but were significantly less than concentrations obtained when cocaine was self-administered by these subjects. [COC] during the sessions were not significantly different between the two days. Baseline [DA]_e were not significantly different between the SA and YC groups or between Day 1 and Day 2. Furthermore, there was no significant difference in the in vitro probe recovery between one and two days following probe implantation. These results suggest that the context in which cocaine was administered significantly altered the neurochemical response to equivalent brain concentrations of cocaine. NAcc [DA]_e was significantly increased when the delivery of cocaine infusions was contingent on the behavior of the rat, indicative of a role in the neural processes underlying cocaine reinforcement. Received: 23 May 1996 / Final version: 11 April 1997     

Choline transporter hemizygosity results in diminished basal extracellular dopamine levels in nucleus accumbens and blunts dopamine elevations following cocaine or nicotine

Dopamine (DA) signaling in the central nervous system mediates the addictive capacities of multiple commonly abused substances, including cocaine, amphetamine, heroin and nicotine. The firing of DA neurons residing in the ventral tegmental area (VTA), and the release of DA by the projections of these neurons in the nucleus accumbens (NAc), is under tight control by cholinergic signaling mediated by nicotinic acetylcholine (ACh) receptors (nAChRs). The capacity for cholinergic signaling is dictated by the availability and activity of the presynaptic, high-affinity, choline transporter (CHT, SLC5A7) that acquires choline in an activity-dependent matter to sustain ACh synthesis. Here, we present evidence that a constitutive loss of CHT expression, mediated by genetic elimination of one copy of the Slc5a7 gene in mice (CHT+/−), leads to a significant reduction in basal extracellular DA levels in the NAc, as measured by in vivo microdialysis. Moreover, CHT heterozygosity results in blunted DA elevations following systemic nicotine or cocaine administration. These findings reinforce a critical role of ACh signaling capacity in both tonic and drug-modulated DA signaling and argue that genetically imposed reductions in CHT that lead to diminished DA signaling may lead to poor responses to reinforcing stimuli, possibly contributing to disorders linked to perturbed cholinergic signaling including depression and attention-deficit hyperactivity disorder (ADHD).     

Disruption of cocaine self-administration following 6-hydroxydopamine lesions of the ventral tegmental area in rats

6-Hydroxydopamine-induced destruction of dopaminergic terminals in the nucleus accumbens have been shown previously to disrupt cocaine and amphetamine self-administration. We sought to determine whether lesions of the DA cell bodies in the ventral tegmental area (VTA) which give rise to the DA innervation of the n. accumbens, would also disrupt cocaine self-administration behavior. Rats were trained to self-inject cocaine (0.75 mg/kg) for 4 hr/day. After a stable baseline was established, one group of rats received bilateral injections of 6-OHDA (4 micrograms/l microliter) into the VTA. Control rats received vehicle injections. When retested on the fifth day post-lesion, all of the 6-OHDA treated animals showed a long lasting reduction in cocaine intake. Three animals did not reinitiate cocaine self-administration after the lesion, although each showed stable post-lesion responding for apomorphine. The surgery had no effect on cocaine self-administration in control animals. These data support the hypothesis that dopaminergic mechanisms are necessary for the normal expression of cocaine self-administration.     

Neuropharmacological evidence for the role of dopamine in ventral pallidum self-stimulation

The present study examines the role of dopaminergic neurotransmission in modulating the reinforcing effect of ventral pallidum (VP) intracranial self-stimulation (ICSS). Fifty four adult rats were implanted with a monopolar moveable stimulating electrode in the VP. Rate-frequency functions were determined by logarithmically decreasing the number of pulses in a stimulation train from a value that sustained maximal responding to one that did not sustain responding. After the ICSS thresholds stabilized, the animals received treatments with several doses of cocaine and of various selective drugs acting at the level of DA receptor subtypes. Their effects on threshold and asymptotic rate were analyzed. Cocaine produced a significant decrease in ICSS threshold but had no significant effect on the asymptotic rate. A significant decrease in ICSS threshold was also seen with the D₃ agonist 7-OH-DPAT. This was associated with a decrease rather than an increase in performance. D₁ and D₂DA receptor blockers (haloperidol, SCH-23390, raclopride and sulpiride) produced a dose dependent increase in ICSS threshold and a decrease in the maximal rate. The results suggest that DA plays a modulatory role in VP intracranial self-stimulation, and that D₁, D₂ and D₃ receptors are involved in the mediation of this effect, although to different extents.     

Effects of halothane anaesthesia on extracellular levels of dopamine,dihydroxyphenylacetic acid,homovanillic acid and 5-hydroxyindolacetic acid in rat striatum: a microdialysis study

Summary The effects of halothane anaesthesia on striatal extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5HIAA) were investigated in microdialysis experiments. Induction of anaesthesia was accompanied by a rapid increase in dopamine levels and a slower increase in DOPAC and HVA. 5HIAA was not affected. The reduction of dopamine levels induced by apomorphine 0.05 mg/kg appeared with a shorter latency in conscious rats than in anaesthetised rats but the maximum decrease was unaffected by anaesthesia. The decreases in dopamine and DOPAC induced by -methyl-p-tyrosine 50 mg/kg were affected in opposite directions by halothane: the dopamine reduction was more pronounced while the DOPAC reduction was less pronounced in anaesthetized than in conscious animals. In no case was a qualitative shift in the response observed. It is concluded that halothane may influence the levels of dopamine as well as the response to dopaminergic drugs.Send offprint requests to L. Ståhle at the above address     

Contributions of prolonged contingent and noncontingent cocaine exposure to enhanced reinstatement of cocaine seeking in rats

Rationale Recent evidence suggests that prolonged cocaine self-administration produces escalation in drug-seeking behavior in rats analogous to the increased intake patterns observed in cocaine-dependent individuals. However, the contributions of prolonged access to cocaine taking vs the pharmacologic effects of the consequent increased cocaine exposure on escalation of drug-seeking behaviors have not been investigated.Objective The present study assessed the effects of these two factors on maintenance of cocaine self-administration and reinstatement of cocaine seeking.Methods Male, Sprague–Dawley rats were trained to self-administer cocaine (0.2 mg/i.v. infusion; FR1) for 1 h per day for 10 sessions followed by short access (1 h/day), contingent long access (6 h/day), or noncontingent long access (1 h contingent + 5 h of yoked cocaine infusions/day; i.e., short access + yoked) to cocaine for 14 daily sessions. All rats underwent extinction training and were subsequently tested for the ability of cocaine-paired cues or a cocaine-priming injection (7.5 mg/kg i.p.) to reinstate extinguished cocaine seeking.Results Rats in all groups maintained stable responding for cocaine reinforcement and subsequently showed significant reinstatement of cocaine-seeking behavior. Conditioned-cued reinstatement was enhanced after the contingent long access and short access + yoked cocaine exposure relative to short access cocaine exposure. Conversely, cocaine-primed reinstatement was enhanced after contingent long-access cocaine exposure relative to the other two conditions.Conclusions Enhanced drug seeking produced by prolonged daily cocaine self-administration is due to a combination of behavioral and pharmacological factors. Specifically, conditioned-cued reinstatement is enhanced by increased cocaine intake and cocaine-primed reinstatement is enhanced by increased cocaine taking.     

Ventral pallidal extracellular fluid levels of dopamine, serotonin, gamma amino butyric acid, and glutamate during cocaine self-administration in rats

RATIONALE: Dopamine innervation of the nucleus accumbens is thought to have a major role in the biological processes underlying cocaine self-administration. Recent data suggest that dopamine innervation of the ventral pallidum (VP) may also play an important role. OBJECTIVES: This experiment was initiated to assess extracellular fluid levels of dopamine (DA), serotonin (5-HT), gamma-aminobutyric acid (GABA), and glutamate (Glu) in the VP of rats self-administering cocaine using in vivo microdialysis. METHODS: Rats were implanted with intravenous jugular catheters and a microdialysis probe guide cannula into the VP and trained to self-administer (SA) three different doses of cocaine during each daily session. Other rats (yoked rats) were surgically prepared in identical fashion and received vehicle infusions during microdialysis sessions when the SA rat to whom they were yoked produced cocaine infusions. When stable baselines of self-administration were obtained, microdialysates were collected during two consecutive daily self-administration sessions. Neurotransmitter levels were measured using HPLC with electrochemical (DA and 5-HT) or fluorescence detection (GABA and Glu). RESULTS: In SA rats, extracellular fluid levels of DA [DA]e and 5-HT [5-HT]e were elevated throughout the session and levels of Glu [Glu]e showed small increases at a few isolated time points during the session. The increases in [DA]e and 15-HT]e were dose-dependent. Extracellular fluid levels of GABA [GABA]e were unchanged, as were levels of all four neurotransmitters in the yoked rats. CONCLUSIONS: These data support a potential role for DA and 5-HT innervations of the VP in intravenous cocaine self-administration.     

Dopamine autoreceptors in the ventral tegmental area show subsensitivity following withdrawal from chronic antidepressant drug treatment

The suppression by apomorphine of food intake and eating time was used to assay the sensitivity of dopamine cell body autoreceptors during the course of treatment with DMI, amitriptyline and mianserin. Brief (2–4 days) DMI treatment enhanced the effects of apomorphine, administered systemically or centrally to DA cell body regions. During chronic DMI treatment (3–7 weeks) some evidence of autoreceptor subsensitivity was observed with systemic apomorphine, but not with central apomorphine. Responses to apomorphine applied systemically were reduced during withdrawal from chronic DMI, and responses to apomorphine applied to the ventral tegmental area were reduced during withdrawal from all three antidepressants. As evidence of DA autoreceptor subsensitivity was only observed reliably during withdrawal, this effect is unlikely to be of clinical importance.     

Effects of chronic buprenorphine treatment on levels of nucleus accumbens glutamate and on the expression of cocaine-induced behavioral sensitization in rats

Rationale

Chronic treatment with the mu-opioid receptor agonist, buprenorphine, reduces cocaine-induced behaviors in rats with a history of cocaine self-administration. The mechanisms underlying these actions of buprenorphine remain unclear.

Objectives

The objective of this study is to investigate the effects of chronic buprenorphine treatment on cocaine-induced activity and levels of glutamate and dopamine (DA) in the nucleus accumbens (NAc) in rats that were preexposed to cocaine or drug-naïve.

Materials and methods

In experiment 1, basal levels of NAc glutamate were assessed using in vivo microdialysis in cocaine-naïve rats that were treated chronically with buprenorphine (3.0 mg/kg per day) via osmotic minipumps or that underwent sham surgery. In experiment 2, rats were preexposed to seven daily injections of cocaine or saline. After a 12–16-day drug-free period, extracellular levels of NAc glutamate and DA and locomotor activity were assessed simultaneously, before and after an acute injection of cocaine (15 mg/kg, intraperitoneal), in rats under sham and chronic buprenorphine (3.0 mg/kg per day) treatment.

Results

Chronic buprenorphine treatment increased basal levels of glutamate in drug-naïve and cocaine-preexposed rats, blocked the expression of locomotor sensitization to cocaine, and potentiated the NAc DA response to acute cocaine in cocaine-preexposed rats.

Conclusions

These findings suggest that buprenorphine may block the expression of cocaine sensitization and other cocaine-related behaviors by increasing basal levels of glutamate in the NAc, which would serve to decrease the effectiveness of cocaine or cocaine-associated cues.     

Effects of nicotine and mecamylamine-induced withdrawal on extracellular dopamine and acetylcholine in the rat nucleus accumbens

RATIONALE: Prior research suggests that high levels of acetylcholine (ACh) in the nucleus accumbens (NAc) are associated with aversive states such as morphine withdrawal, but this has not been tested for nicotine withdrawal. OBJECTIVES: The goal was to test the hypothesis that acute nicotine decreases extracellular ACh and increases extracellular dopamine (DA) in the NAc, while withdrawal from nicotine causes an opposite neurochemical imbalance with high extracellular ACh and low DA. METHODS: Rats were prepared with a microdialysis probe in the NAc (primarily the shell region). They received one injection of nicotine (0.5 mg/kg, s.c.) or chronic nicotine (9 mg/kg per day via osmotic minipump). RESULTS: Naive animals receiving acute nicotine showed a mild, significant increase in both ACh (122% of baseline) and DA (124%). After chronic nicotine administration for 7 days, the nicotinic antagonist mecamylamine (1.0 mg/kg, s.c.) precipitated withdrawal with the appearance of somatic signs (teeth chattering and shakes/tremors) and a significant increase in extracellular ACh to 125% of baseline, while extracellular DA decreased to 65%. Control groups receiving saline in place of nicotine or mecamylamine did not show these effects. CONCLUSIONS: Earlier work suggests that the observed release of accumbens ACh and DA in response to acute nicotine administration may be a factor in nicotine-induced suppression of appetite. ACh release during withdrawal, coupled with the decrease in extracellular DA may play a role in the aversive aspects of nicotine withdrawal that contribute to dependency.     

Extracellular dopamine, norepinephrine, and serotonin in the ventral tegmental area and nucleus accumbens of freely moving rats during intracerebral dialysis following systemic administration of cocaine and other uptake blockers

Extracellular levels of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) were measured by microdialysis in conscious rats equipped with dual probes, one in the ventral tegmental area (VTA) and another one in the contralateral nucleus accumbens (NACC). Dialysate content of all amines in both regions was essentially abolished by local infusion of tetrodotoxin (1 μM) or Ca²⁺-free buffer. Injection of the selective DA uptake blocker GBR 12935 (15 mg/kg IP) increased DA, as well as NE and, to a lesser extent, 5-HT in the VTA; it increased DA more than 5-HT in the NACC. The selective NE uptake blocker desipramine (10 mg/kg IP) increased NE but also 5-HT in the VTA and NACC; the DA level was persistently enhanced in the VTA, whereas in the NACC it initially rose and then fell below baseline value. The selective 5-HT uptake blocker citalopram (15 mg/kg IP) was generally more effective in elevating dialysate level of 5-HT than that of other amines in both regions. Cocaine (20 mg/kg IP) was non-selective in enhancing all three amines in both regions. There is considerable crosstalk between monoamine systems occurring upon systemic administration of uptake blockers, and the VTA and NACC are notably different in the time course of the DA effect (long-lasting versus transient). Received: 25 February 1997 /Final version: 2 June 1997     

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Rationale Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear.Objectives To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration.Methods In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0).Results Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions.Conclusions Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.     

Involvement of dopamine in the aversive stimulus properties of cocaine in rats

Previous studies of cocaine self-administration have demonstrated central dopaminergic involvement in cocaine's positive reinforcing properties. The present study reports the ability of pimozide, a dopamine receptor antagonist, to attenuate a conditioned taste aversion induced by repeated injections of cocaine. Rats placed on a daily water deprivation schedule were subsequently presented with a novel saccharin taste in their drinking fluid immediately followed by administration of four 9 mg/kg injections of cocaine spaced at 20 min intervals. These animals exhibited a reduction in saccharin intake on subsequent presentations. Animals pretreated with pimozide 90 min prior to the saccharin-cocaine pairings failed to show this reduction. In a second experiment using an identical procedure, repeated injections of lithium chloride were shown to induce a CTA both in pimozide-pretreated and control animals. The results of these two experiments are consistent with the notion that a functional relationship may exist between neurochemical mechanisms underlying both the aversive (CTA-inducing) and positive reinforcing properties of self-administered drugs such as cocaine.     

Behavioral and neurochemical effects of cocaine and diphenhydramine combinations in rhesus monkeys

Rationale  Diphenhydramine (DPH) is an over-the-counter medication used in the treatment of allergic symptoms. While DPH abuse is infrequent, recent preclinical evidence suggests that DPH and cocaine combinations may have enhanced reinforcing properties. Objective  The aims were to assess the reinforcing effectiveness of cocaine and DPH alone or in combination under a second-order schedule of reinforcement and to examine the neurochemical basis of this interaction using in vivo microdialysis in awake rhesus monkeys. Materials and methods  Cocaine (0.03–0.3 mg/kg per injection), DPH (0.3–3.0 mg/kg per injection), or a combination was available under a second-order schedule of intravenous drug reinforcement (n = 3). In microdialysis studies, noncontingent cocaine (0.1–1.0 mg/kg, iv), DPH (1.7 and 3.0 mg/kg, iv), or a combination was administered and changes in extracellular dopamine levels in the caudate nucleus were examined (n = 3–5). Results  Cocaine and DPH dose-dependently maintained operant responding. Dose combinations of 1.0 or 1.7 mg/kg per injection DPH and 0.03 mg/kg per injection cocaine maintained greater rates of operant responding than 0.03 mg/kg per injection cocaine alone in the second component of the behavioral session. In microdialysis studies, cocaine dose-dependently increased extracellular dopamine levels, but no dose of DPH tested significantly increased dopamine levels above baseline. Moreover, combining DPH with cocaine did not enhance cocaine-induced dopamine increases. Conclusions  The results support previous evidence of enhanced reinforcement with cocaine and DPH combinations and extend this finding to operant behavior maintained under a second-order schedule. However, the reinforcing effects of DPH alone or in combination with cocaine do not appear to be mediated via changes in dopamine overflow. Banks and Andersen contributed equally to this work.