Neural Mechanisms of Drug Reinforcementa

We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dosedependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

Section: Effects Of Cocaine During Chronic Exposure To Heroin and Dursupporting

confidence: 89%

Effects of Cocaine in Rats Exposed to Heroin

Leri

Flores

Rajabi

et al. 2003

“…The endogenous opioid neuropeptide most associated with regulating hedonic state is enkephalin (Skoubis et al, 2005), and the NAc (in particular the shell division) is the most limbic-related striatal subregion tightly coupled with reward behavior (Everitt and Wolf, 2002;Koob, 1992). The selective enhancement of PENK mRNA expression in the NAc shell could potentially underlie the altered heroin Proenkephalin mRNA expression levels (expressed as d.p.m./ mg; mean7SEM) in the caudate-putamen (C-P), nucleus accumbens (NAc) core, and NAc shell of adult rats with adolescent exposure to THC or vehicle.…”

Section: Discussionmentioning

confidence: 99%

“…For example, animals lacking the type-1 cannabinoid receptor (CB 1 ; mediates the neural actions of cannabinoids) gene do not self-administer heroin Ledent et al, 1999) or develop morphine-induced conditioned place preference. Acute administration of D-9-tetrahydrocannabinol (THC; psychoactive component of cannabis) elevates b-endorphin and enkephalin peptide levels in the ventral tegmental area (VTA; (Solinas et al, 2004b) and nucleus accumbens (NAc; (Navarro et al, 2001), key neuroanatomical substrates for reward (Everitt and Wolf, 2002;Koob, 1992). Moreover, CB 1 and m opioid receptors (mORs; mediates heroin's actions) are localized on similar neurons in the striatum and VTA, which modulate reward and motor behaviors (Pickel et al, 2004;Rodriguez et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Adolescent Cannabis Exposure Alters Opiate Intake and Opioid Limbic Neuronal Populations in Adult Rats

Ellgren

Spano

Hurd

2006

257

208

Cannabis use is a hypothesized gateway to subsequent abuse of other drugs such as heroin. We currently assessed whether D-9-tetrahydrocannabinol (THC) exposure during adolescence modulates opiate reinforcement and opioid neural systems in adulthood. Long-Evan male rats received THC (1.5 mg/kg intraperitoneally (i.p.)) or vehicle every third day during postnatal days (PNDs) 28-49. Heroin self-administration behavior (fixed ratio-1; 3-h sessions) was studied from young adulthood (PND 57) into full adults (PND 102). THC-pretreated rats showed an upward shift throughout the heroin self-administration acquisition (30 mg/kg/infusion) phase, whereas control animals maintained the same pattern once stable intake was obtained. Heightened opiate sensitivity in THC animals was also evidenced by higher heroin consumption during the maintenance phase (30 and 60 mg/kg/infusion) and greater responding for moderate-low heroin doses (dose-response curve: 7.5, 15, 30, 60, and 100 mg/kg/injection). Specific disturbance of the endogenous opioid system was also apparent in the brain of adults with adolescent THC exposure. Striatal preproenkephalin mRNA expression was exclusively increased in the nucleus accumbens (NAc) shell; the relative elevation of preproenkephalin mRNA in the THC rats was maintained even after heroin self-administration. Moreover, m opioid receptor (mOR) GTP-coupling was potentiated in mesolimbic and nigrostriatal brainstem regions in THC-pretreated animals. mOR function in the NAc shell was specifically correlated to heroin intake. The current findings support the gateway hypothesis demonstrating that adolescence cannabis exposure has an enduring impact on hedonic processing resulting in enhanced opiate intake, possibly as a consequence of alterations in limbic opioid neuronal populations.

“…All addictive drugs increase the levels of synaptic dopamine released at nerve terminals within the NAc (Di Chiara and Imperato, 1988;Koob, 1992;Nestler, 1992). Glutamate controls many aspects of dopamine cell function, including midbrain dopamine cell firing and dopamine release.…”

Section: Nmdar-dependent Ltp Of Field Potentials Presents a Simpler Mmentioning

confidence: 99%

High-Frequency Afferent Stimulation Induces Long-Term Potentiation of Field Potentials in the Ventral Tegmental Area

Nugent

Hwong

Udaka

et al. 2007

Excitatory synapses on dopamine neurons in the VTA can undergo both long-term potentiation and depression. Additionally, druginduced plasticity has been found at VTA synapses, and is proposed to play a role in reward-related learning and addiction by modifying dopamine cell firing. LTP at these synapses is difficult to generate experimentally in that it requires an undisturbed intracellular milieu and is often small in magnitude. Here, we demonstrate the induction of LTP as a property of evoked field potentials within the VTA. Excitatory field potentials were recorded extracellularly from VTA neurons in acute horizontal midbrain slices. Using extracellular and intracellular recording techniques, we found that evoked field potentials originate within the VTA itself and are largely composed of AMPA receptor-mediated EPSPs and action potentials triggered by activation of glutamatergic synapses on both dopamine and GABA neurons. High-frequency afferent stimulation (HFS) induced LTP of the field potential. The induction of this LTP was blocked by application of the NMDAR antagonist, d-APV, prior to HFS. As reported previously, glutamatergic synapses on GABA neurons did not express LTP while those on dopamine neurons did. We conclude that the potentiation of glutamatergic synapses on dopamine neurons is a major contributor to NMDA receptor-dependent LTP of the field potential. Field potential recordings may provide a convenient approach to explore the basic electrophysiological properties of VTA neurons and the development of addiction-related processes in this brain region.