Heroin Administration Research Articles

Heroin smoking and heroin using trends in Norway

A.L. Bretteville & A. Skretting: Heroin smoking and heroin using trends in Norway The aim is to ascertain whether new ways of administering heroin have gained ground in Norway by examining three series of cross-sectional surveys (D1–D3). D1–D2 are based on postal questionnaires for which D1 is a representative sample of 15–20 year olds in Oslo (1968–2006) and D2 is a corresponding sample of 21–30 year olds (1998, 2002, 2006). D3 is based on personal interviews and consists of users of a needle-exchange service in Oslo (1993–2008). Despite a substantial rise in illegal drug use over the study period, there is no indication of increased heroin use by young people. The prevalence rates are relatively low for all heroin use (1–2%). Routes of heroin administration seem to have changed, however, as more young people (21–30 years) now report having smoked heroin and fewer report having injected the drug. There also seem to be changes in drug use patterns among current injecting drug users (IDUs). Splitting the sample by year of injection debut, we find among those starting since year 2000; i) a rise in average injection debut age of 10 years (25.6 versus 15.5 years); ii) a higher proportion with heroin smoking experience (74% versus 53%); and iii) a higher proportion having smoked heroin before injecting the drug (73% versus 16%), compared to the IDUs debuting before 1980. Consequently, the data suggest changes in drug use patterns, particularly heroin use, among recreational users and heavy drug users. So, in addition to an increase in the number of IDUs, it seems likely that the number of heroin smokers has risen too.

Heroin-induced changes of CD34-positive rat thymus cells

Heroin is a well known opioid that causes al-terations to the immune system of a number of investigated animals. Only a few studies have explored the effect of heroin on the lymphocytes maturation. Thymocyte progenitors originate from haematopoietic stem cells in the bone marrow. The immature T-cells express neither CD4 nor CD8, and are therefore classed as double-negative (CD4-CD8-) cells. CD34 glycoprotein is the only defined marker of the immature T-lymphocytes. In this study we have investigated the changes induced in CD34+ rat thymocytes after heroin administration by immunofluores-cence in frozen rat thymus sections using the 4H11 monoclonal anti-CD34 antibody. There is a remarkable decrease in the number of CD34+ immature thymocytes when examined 1hour after last heroin injection and a small recover when examination took place 20 days after last injection. The above results suggest a major effect of heroin administration early in the ma- turation process of T lymphocytes probably by increasing the apoptotic cell death and the ne- gative consequences for the immune system responses.

Increased Locomotor Activity Induced by Heroin in Mice: Pharmacokinetic Demonstration of Heroin Acting as a Prodrug for the Mediator 6-Monoacetylmorphine in Vivo

We investigated the relative importance of heroin and its metabolites in eliciting a behavioral response in mice by studying the relationship between concentrations of heroin, 6-monoacetylmorphine (6MAM), and morphine in brain tissue and the effects on locomotor activity. Low doses (subcutaneous) of heroin (< or =5 micromol/kg) or 6MAM (< or =15 micromol/kg) made the mice run significantly more than mice given equimolar doses of morphine. There were no differences in the response between heroin and 6MAM, although we observed a shift to the left of the dose-response curve for the maximal response of heroin. The behavioral responses were abolished by pretreatment with 1 mg/kg naltrexone. Heroin was detected in brain tissue after injection, but the levels were low and its presence too short-lived to be responsible for the behavioral response observed. The concentration of 6MAM in brain tissue increased shortly after administration of both heroin and 6MAM and the concentration changes during the first hour roughly reflected the changes in locomotor activity. Both the maximal and the total concentration of 6MAM were higher after administration of heroin than after administration of 6MAM itself. The morphine concentration increased slowly after injection and could not explain the immediate behavioral response. In summary, the locomotor activity response after injection of heroin was mediated by 6MAM, which increased shortly after administration. Heroin acted as an effective prodrug. The concentration of morphine was too low to stimulate the immediate response observed but might have an effect on the later part of the heroin-induced behavioral response curve.

Self administration of heroin and cocaine in morphine-dependent and morphine-withdrawn rhesus monkeys

Dependence can develop during chronic opioid use, and the emergence of withdrawal might promote drug taking. This study examined how chronic morphine administration or withdrawal modified self administration of heroin or cocaine. Four monkeys responded under a fixed ratio 10 schedule to receive i.v. infusions of heroin (0.56-560 microg/kg/infusion) or cocaine (1-100 microg/kg/infusion). Monkeys received morphine twice daily; the final dose was 10 mg/kg/12 h. Dose-effect curves for heroin or cocaine were determined in 150-min sessions throughout morphine administration and during temporary suspension when withdrawal signs were also monitored. Heroin dose-effect curves and withdrawal signs were determined daily following termination of morphine administration. Before monkeys received morphine, heroin, and cocaine maintained responding with unit doses of 1.78 microg/kg of heroin and 10 microg/kg/injection of cocaine resulting in, on average, 13.4 and 20.8 infusions, respectively. When monkeys received morphine daily, self administration of heroin and cocaine decreased to, on average, 3.1 and 11.3 infusions, respectively. Responding for heroin or cocaine recovered following temporary (17-53 h) suspension of morphine administration. The number of heroin infusions and total withdrawal signs increased when morphine administration was terminated. Withdrawal signs peaked 3-4 days after morphine; however, the number of infusions remained elevated for 8 weeks. Changes in self administration responding did not precisely covary with signs of withdrawal and responding for small doses of heroin persisted long after discontinuation of morphine, suggesting that non-pharmacologic (e.g., conditioned reinforcing) effects might contribute to the maintenance of lever pressing under these conditions.

Enhancing effect of heroin on social recognition learning in male Sprague–Dawley rats: modulation by heroin pre-exposure

There is evidence that pre-exposure to drugs of abuse can induce sensitization to several of their effects. Four experiments were conducted to investigate the effect of heroin pre-exposure on modulation of memory consolidation as indexed by heroin's action on rate of learning. Male Sprague-Dawley rats were tested on a social recognition learning task which assesses changes in investigation during repeated exposure to the same rat (habituation training: four sessions) and during exposure to a novel rat (dishabituation test). In the first experiment, rats received 0, 0.3, or 1 mg/kg heroin s.c. immediately following each training session, or 1 mg/kg heroin 2 h post-training. In experiments 2 and 3, rats received 1 mg/kg heroin post-training after a 7-day drug-free period from heroin pre-exposure achieved through conditioned place preference (1 mg/kg s.c., 1 injection/day x 4 days) or intravenous self-administration (0.05 mg/kg/infusion i.v., 3 h/day x 9 days) training. In experiment 4, rats received 0, 0.03, 0.3, or 3 mg/kg heroin post-training after a 7-day drug-free period from a regimen of heroin administration (i.e., 1 mg/kg heroin/day s.c. x 7 days) that induced locomotor sensitization. Post-training administration of heroin enhanced social recognition learning in a dose- and time-dependent manner. Importantly, no regimen of heroin pre-exposure significantly altered this effect of heroin. These results do not support the hypothesis that heroin pre-exposure leads to sensitization to its effect on memory consolidation of non-drug-related learning. However, this requires further testing using alternative heroin pre-exposure regimens, a wider range of post-training heroin doses, as well as other types of learning tasks.

Problematic heroin use incidence trends in Spain

To estimate the annual incidence of heroin use in Spain. Data on individuals' year of first heroin use (from 1971 to 2005), year of first heroin treatment between 1991 and 2005 and most frequent route of heroin administration when presenting to treatment were obtained from the Spanish Drug Observatory Register and used to calculate the delay between onset and treatment. By using a log-linear model approach it was possible to correct for missing observations (heroin users who presented for treatment before 1991 and those who had still not presented by the end of 2005) and to estimate heroin incidence over time. The estimated incidence of problematic heroin use in the population aged 15-44 peaked at 190 per 100,000 in 1980--after rising rapidly from less than 40 per 100,000 in 1971--and fell subsequently to about 8 per 100,000 in 2005. On average, incidence was five times higher in men. Injecting heroin incidence peaked and declined rapidly from 1980; as heroin smoking did not decline as rapidly, from 1985 onwards its estimated incidence has remained above that of heroin injecting. The delay between starting heroin use and entering treatment had a median of 3 years. We demonstrate the utility of a method to estimate heroin incidence from analysis of observed trends in presentations at specialist drug treatment facilities. The estimates suggest that incidence of heroin use, especially injecting, has fallen since 1980 and is now lower than in the early 1970s.

Alterations of prodynorphin gene expression in the rat mesocorticolimbic system during heroin self-administration

Opiate-induced alterations in the gene expression of the opioid propeptides prodynorphin (PDYN) and proenkephalin (PENK) in the brain have previously been described. However, there are no studies examining opioid propeptide system alterations due to long-lasting heroin self-administration. In our study, using in situ hybridization, we measured PDYN and PENK mRNA levels in the dorsal striatum, central nucleus of amygdala (CEA), and nucleus accumbens (NAcc) shell and core in rats after 6 weeks of heroin self-administration (fixed ratio 5, 0.02 mg/kg/infusion of heroin i.v.) and their respective saline or heroin “yoked” control. Our results show an increase in the PDYN mRNA level in the CEA and NAcc shell and no changes of PENK gene expression after heroin self-administration. In addition, to dissociate pharmacological effects of heroin from those produced by motivational processes driving active heroin intake on the PDYN and PENK gene expression, we compared effects of response-dependent (contingent) and response-independent (noncontingent — “yoked” heroin control) heroin administration. We found no differences between contingent and noncontingent groups of rats. In conclusion, our results indicate neuroadaptations in the PDYN but not PENK gene expression in rat limbic forebrain during heroin self-administration. We show that such changes depend on direct pharmacological actions of heroin rather than contingent heroin intake. These neuroalterations probably occur as an adaptation to long-lasting heroin exposure and may underlie changes leading to compulsive drug use and addiction.

Conditioned effects of heroin on proinflammatory mediators require the basolateral amygdala

Heroin administration alters the induction of nitric oxide, a molecule known to play a critical role in immune function. Previous research has shown that these alterations can be conditioned to environmental stimuli that have been associated with drug administration. Little is known about the brain areas that mediate these effects; however, the basolateral amygdala (BLA) has been implicated in the formation of stimulus-reward associations within models of drug abuse. The present study sought to determine whether inactivation of the BLA would alter heroin's conditioned effects on the expression of inducible nitric oxide synthase (iNOS) and the proinflammatory cytokines TNF-alpha and IL-1beta in the rat. The conditioning procedure involved repeated pairing of heroin with placement into a standard conditioning chamber. To test the conditioned response, animals were returned to the previously drug-paired environment 6 days after the final conditioning session. Prior to testing, animals received intra-BLA microinfusions of a mixture of the GABA agonists muscimol and baclofen. Following removal from the chambers on test day, all animals received subcutaneous lipopolysaccharide to induce systemic expression of iNOS, TNF-alpha and IL-1beta. Analyses using real-time RT-PCR indicated that inactivation of the BLA blocked the suppressive effect of heroin-associated environmental stimuli on iNOS induction and on the expression of the proinflammatory cytokines TNF-alpha and IL-1beta in spleen and liver tissue. This study is important because it is the first to demonstrate that heroin's conditioned effects on proinflammatory mediators require the BLA. These findings may have significant implications for the treatment of heroin users.

Mu opioid receptor knockdown in the substantia nigra/ventral tegmental area by synthetic small interfering RNA blocks the rewarding and locomotor effects of heroin

Mu opioid receptors (MOP-r) play an important role in the rewarding and locomotor stimulatory effects of heroin. The aim of the current study was to determine whether infusion of small interfering RNAs (siRNA) targeting MOP-r into the midbrain could knock down MOP-r mRNA and affect heroin-induced locomotor activity or heroin-induced conditioned place preference. Ten-week-old male C57BL/6J mice were surgically implanted bilaterally with guide cannulae directed between the substantia nigra and ventral tegmental area. After 4 days' recovery, mice were infused bilaterally with siRNAs that target the MOP-r (2 mM×0.75 μl/side/day for 3 days) or control siRNA. Seven days after the last infusion, a procedure for conditioned place preference was begun with four heroin (3 mg/kg i.p.) administration sessions alternating with four saline sessions. While heroin induced an increase in locomotor activity in all groups, siRNAs targeting specific regions of MOP-r significantly attenuated this effect. Of particular interest, mice infused with specific siRNAs targeting the MOP-r failed to develop and express conditioned place preference to heroin, or showed a significantly attenuated preference. These alterations in reward-related behaviors are likely due to the reduction in MOP-r mRNA and protein, shown in separate studies by in situ hybridization and autoradiography using the same MOP-r- siRNA infusions. Taken together, these studies demonstrate the utility of siRNA in the neurobiological study of specific components of the reward system and should contribute to the study of other complex behaviors.

The α 1 adrenergic receptor antagonist prazosin reduces heroin self-administration in rats with extended access to heroin administration

Previous studies have reported that noradrenergic antagonists alleviate some of the symptoms of opiate withdrawal and dependence. Clinical studies also have shown that modification of the noradrenergic system may help protect patients from relapse. The present study tested the hypothesis that a dysregulated noradrenergic system has motivational significance in heroin self-administration of dependent rats. Prazosin, an α 1-adrenergic antagonist (0.5, 1.0, 1.5 and 2.0 mg/kg, i.p.), was administered to adult male Wistar rats with a history of limited (1 h/day; short access) or extended (12 h/day; long access) access to intravenous heroin self-administration. Prazosin dose-dependently reduced heroin self-administration in long-access rats but not short-access rats, with 2 mg/kg of systemic prazosin significantly decreasing 1 h and 2 h heroin intake. Prazosin also reversed some changes in meal pattern associated with extended heroin access, including the taking of smaller and briefer meals (at 3 h), while also increasing total food intake and slowing the eating rate within meals (both 3 h and 12 h). Thus, prazosin appears to stimulate food intake in extended access rats by restoring meals to the normal size and duration. The data suggest that the α 1 adrenergic system may contribute to mechanisms that promote dependence in rats with extended access.

Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior

In the accompanying paper, we described incubation of heroin-seeking behavior in rats following 14 days of abstinence. To gain an understanding of genomic changes that accompany this behavioral observation, we measured the expression of genes previously reported to respond to drugs of abuse. Specifically, after 1 or 14 days of abstinence, mRNA expression was measured for 11 genes in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) immediately following a single 90 min extinction session. Additionally, the role of contingency was examined in control rats that received yoked, response-independent heroin administration. Gene expression was quantified by real-time quantitative PCR. Expression of five genes (Arc, EGR1, EGR2, Fos, and Homer1b/c) was changed in the mPFC. EGR1 and EGR2 expression was increased following the 90 min extinction session in a contingency-specific manner and this increase persisted through the 14 days of abstinence. Fos expression was also increased after 1 and 14 days of abstinence, but at 14 days this increase was response-independent (i.e., it occurred in both the rats with a history of heroin self-administration and in the yoked controls). Arc expression increased following the extinction session only in rats with a history of heroin self-administration and only when tested following 1, but not 14, days of abstinence. Homer 1 b/c decreased after 14 days of enforced abstinence in rats that received non-contingent heroin. Expression of only a single gene (EGR2) was increased in the NAc. These data demonstrate that behavioral incubation is coincident with altered levels of specific transcripts and that this response is contingently-specific. Moreover, EGR1 and EGR2 are specifically upregulated in self-administering rats following extinction and this finding persists through 14 days of abstinence, suggesting that these genes are particularly associated with the incubation phenomenon. These latter observations of persistent changes in gene expression following abstinence may reflect molecular correlates of relapse liability.

Injecting and Noninjecting Heroin Administration: Transitions and Treatment Outcomes across 36 Months

To examine long-term stability in route of administration and treatment outcomes for noninjecting (NIHU) and injecting (IHU) heroin users, a cohort of 429 heroin users were followed over 36 months. Across follow-up, 35.3% of NIHU injected heroin and a transition to primary heroin injecting was made by 8.5%. Amongst IHU, 11.1% smoked heroin and a transition to primary heroin smoking was made by 2.3%. While NIHU were less likely to be in treatment at 36 months, there were no differences in overall treatment exposure. At 36 months, there were no differences in heroin use, polydrug use, crime, physical health, or psychopathology. NIHU were, however, less likely to be injecting and to have injection-related health problems. It is concluded that there is a substantial risk of injecting occurring amongst NIHU and that route of administration does not differentially predict long-term treatment response.

Facilitation of avoidance behaviour in mice chronically treated with heroin or methadone

Although the repercussion of chronic treatment with large amounts of opioids on cognitive performance is a matter of concern, the effects of opioid drugs on passive avoidance learning have been scarcely studied. Here, we analyzed the effects of prolonged administration of heroin and methadone, as well as the impact of suffering repeated episodes of withdrawal on fear-motivated learning using the passive avoidance test. Mice received chronic treatment (39 days) with methadone (10mg/kg/24h), associated or not with repeated withdrawal episodes, or with heroin (5mg/kg/12h). Our results show that, regardless of the type of treatment received, all mice displayed similar basal thermal nociceptive thresholds during 25 days of treatment. In the hot plate test, both methadone and heroin induced antinociception 30min after drug administration. The analgesic effect was absent when measured 4h after heroin and 12h after methadone. Pain behavioural responses elicited by growing intensities of electric shock, applied on day 28th of treatment, were similar in all groups of mice. Our results indicate that chronic opioid treatment had promnesic effects on passive avoidance behaviour in mice, unrelated to changes in the nociceptive state.

Different time schedules affect conditioned place preference after morphine and morphine-6-glucuronide administration

A number of studies have investigated the reward potential of morphine, using the Conditioned Place Preference (CPP) procedure. The morphine-metabolite morphine-6-glucuronide (M6G) is known to have analgesic activity comparable to morphine, but its reward properties are unclear. An unbiased two compartment counterbalanced procedure was used to investigate the induction of CPP by morphine or M6G in C57BL/6J-Bom mice using different conditioning schedules. The conditioning sessions took place either immediately after the injections and lasted either 20 or 40 min, or were delayed until 15 min after the injections and lasted for 20 min. Locomotor activity was recorded during the conditioning sessions. Morphine induced CPP when the 20-minute conditioning sessions were conducted directly after the injections, but not when they were delayed. M6G induced CPP when the 20-minute conditioning sessions were delayed, but not when the animals were conditioned directly after the injections. Neither morphine nor M6G induced CPP after 40-minute direct conditioning sessions. M6G had a biphasic effect on locomotor activity, with an initial decrease followed by excitation. This study indicates that M6G has rewarding effects, and might contribute to the development of addiction after heroin or morphine administration. However, in any attempts to explore the reward properties of M6G, the choice of time schedule should be carefully considered.

Cerebral blood flow effects of acute intravenous heroin administration

We examined acute effects of intravenous diacetylmorphine (heroin) administration — which induces a characteristic biphasic response: A short rush-sensation associated with intense pleasurable feelings followed by a subjectively different period of euphoria on cerebral blood flow. This was assessed in nine male heroin dependent patients participating in a heroin maintenance program in a setting resembling everyday pattern of heroin abuse. 99mTc-HMPAO was administered 45 s (rush) and 15 min (euphoria) after administration of i.v. heroin and 45 s after administration of saline (placebo). Plasma concentration of diacetylmorphine and its metabolites were measured with high-pressure liquid chromatography (HPLC). Compared to the euphoria condition, rush was associated with blood flow increase in the left posterior cerebellar lobe, left anterior cingulate gyrus and right precuneus. Our results are in line with recent reports indicating that the cerebellum is an important component in functional brain systems subserving sensory and motor integration, learning, modulation of affect, motivation and social behaviour, which all play important roles in reinforcing properties of opioids.

Chronic administration of heroin to mice produces up-regulation of brain apoptosis-related proteins and impairs spatial learning and memory

Several studies open up the possibility that chronic exposure to opioid drugs in the CNS would interfere with learning and memory through a neurotoxic effect related to activation of apoptotic pathways. Here, we have analyzed the effects of prolonged heroin administration on sensorimotor and cognitive performance in mice, as well as the associated changes in brain expression of proteins regulating the extrinsic (FasL and Fas) and the mitochondrial (Bcl-2, Bcl-X L, Bad and Bax) apoptotic pathways. Our findings indicate that chronic heroin did not interfere with mice performance in a battery of sensorimotor tests. On the other hand, cognitive ability in the Morris water maze and cognitive flexibility-related performance were strongly impaired by chronic heroin. These effects were associated with up-regulation of pro-apoptotic proteins such as Fas, FasL and Bad, in the cortex and hippocampus, indicating the activation of both the death receptor and the mitochondrial apoptotic pathways. Another indicator of apoptosis was the presence of TUNEL (TdT-mediated dUTP nick-end labeling) positive cells scattered throughout the brain.

Encuesta a personas admitidas a tratamiento por abuso o dependencia de heroína o cocaína, 2003-2004

Objetive To know the sociodemographic characteristics, consumption patterns, major risk behaviors in HIV transmission, prevalence of HIV infection, and utilization of health resources among cocaine and heroine drug users entering treatment Methods A cross-sectional survey consisting of a personal interview was conducted on a systematic sample of 2610 admitted to outpatient drug treatment during 2003-2004 in all Spanish autonomous regions, except for Basque Country and Navarra. Results Among all participants, 80.3% were males. Mean age was 32.7 years. A 42.5% was unemployed and frequently got money from family, partner, social support and criminal activities. The most frequent route of heroin administration was smoking. Most drug users consumed several drugs. Siblings, partners, flatmates and friends of participants usually consumed drugs. Among all participants, 43.0% had ever injected drugs, and 23.4% had injected drugs during the year before treatment admission. From these last-year injectors, 21.4% had taken used syringes from others. From all participants, just 30.2% had always used a condom during previous year when they had a sexual intercourse with a casual partner. At admission, 17.9% reported that they were HIV positives. This rate was higher among ever injectors (29.4%). Comparing these results with a similar survey carried out in 1996, the use of intravenous drugs is less common among heroin drug users, as well as the use of syringes used previously by others (34% in 1996 had taken used syringes during the last year versus. 20.1% in 2003-2004). HIV infection rate has also decreased slightly in this period. Conclusions Although some positive changes have occurred since 1996 among patients admitted to heroin treatment, this survey shows that is necessary to carry out different measures in order to improve social situation and prevention of HIV transmission.

More free syringes, fewer drug injectors in the case of Spain

International policy on the prevention of HIV and other health problems among drug users should be guided by scientific evidence. However, it has frequently been argued that Needle Exchange Programs (NEPs) have negative effects such as facilitation of injection of illicit drugs, without providing evidence to support this hypothesis. Since the early 1980s Spain has experienced a severe HIV epidemic among drug injectors. A delayed but comprehensive implementation of harm reduction programs has taken place since the early 1990s. This paper assesses trends between 1991 and 2004, both in the number of sterile syringes exchanged or delivered by NEPs or other programs to improve injectors’ access to sterile injection material, and in the number of injectors admitted to first treatment for heroin or cocaine dependence, as a proxy for trends in the number of new drug injectors in Spain. The results show increased access to sterile syringes and a sharp decrease in the number of new drug injectors, suggesting that NEPs have not promoted drug injection. A positive overall transition from injecting to smoking was also observed in the most frequent route of heroin or cocaine administration.

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

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. 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. 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. 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. 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.

P.1.006 GABA receptors can play different roles at the beginning and development of sexual motivation

C57BL/6J and 129 substrains of mice are known to differ in their basal levels of anxiety and behavioral response to drugs of abuse. We have previously shown strain differences in heroin-induced conditioned place preference (CPP) between C57BL/6J (C57) and 129P3/J (129) mice, and in the regional expression of several receptor and peptide mRNAs. In this study, we examined the contribution of the GABAergic system in the cortex, nucleus accumbens (NAc), caudate putamen (CPu) and the region containing the substantia nigra and ventral tegmental area (SN/VTA) to heroin reward by measuring mRNA levels of 7 of the most commonly expressed GABA-A receptor subunits, and both GABA-B receptor subunits, in these same mice following saline (control) or heroin administration in a CPP design. Using real-time PCR, we studied the effects of strain and heroin administration on GABA-A α1, α2, α3, β2, and γ2 subunits, which typically constitute synaptic GABA-A receptors, GABA-A α4 and δ subunits, which typically constitute extrasynaptic GABA-A receptors, and GABA-B R1 and R2 subunits. In saline-treated animals, we found an experiment-wise significant strain difference in GABA-Aα2 mRNA expression in the SN/VTA. Point-wise significant strain differences were also observed in GABA-Aα2, GABA-Aα3, and GABA-Aα4 mRNA expression in the NAc, as well as GABA-BR2 mRNA expression in the NAc and CPu, and GABA-BR1 mRNA expression in the cortex. For all differences, 129 mice had higher mRNA expression compared to C57 animals, with the exception of GABA-BR1 mRNA in the cortex where we observed lower levels in 129 mice. Therefore, it may be possible that known behavioral differences between these two strains are, in part, due to differences in their GABAergic systems. While we did not find heroin dose-related changes in mRNA expression levels in C57 mice, we did observe dose-related differences in 129 mice. These results may relate to our earlier behavioral finding that 129 mice are hyporesponsive to the rewarding effects of heroin.