Cellular responses of nucleus accumbens neurons to opiate-seeking behavior: i. sustained responding during heroin self-administration

Abstract

The nucleus accumbens (NAcc) has been hypothesized to be a critical component of the circuit mediating opiate-seeking behaviors. To further explore the electrophysiological correlates of opiate-seeking behavior, we recorded neurons in the NAcc and in the medial prefrontal cortex (mPFC) of rats trained to self-administer heroin for at least 2 weeks. Rats were trained to lever press (FR-1 schedule) for an intravenous (i.v.) infusion of heroin (0.06 mg/kg/injection) in an operant chamber. Spontaneous single unit activity in the NAcc and the mPFC was then recorded while animals were allowed to self-administer heroin. Our data suggest that about 20% (8/42) of the NAcc neurons studied exhibited an inhibitory response immediately after heroin self-administration. However, most of the NAcc neurons studied (76%; 32/42) were not affected during heroin self-administration. In contrast, noncontingent injection of a similar dose of heroin (0.06 mg/kg/injection) had no effect on NAcc spontaneous activity (0/6). On the other hand, passive administration of higher doses of heroin (0.2-0.6/mg/kg/injection) markedly suppressed the firing rate in 46% (6/13) of the neurons studied. These effects of heroin on NAcc activity were antagonized by systemic administration ofnaloxone (4-6 mg/kg, i.v.). Studies characterizing the responses of mPFC neurons during heroin self-administration showed that 40% (2/5) of the neurons tested exhibited an inhibitory effect immediately after heroin self-administration. These data suggest that in animals well-trained to self-administer heroin, only a small number (20%) of the NAcc neurons studied responded to heroin self-administration. Further research is necessary to determine whether these responses are a function of the opiate-seeking state of the animal and the mechanism(s) responsible for these effects of heroin.

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

“…Consistent with this hypothesis, self-or local administration of morphine or heroin into the NAc significantly suppresses the spontaneous firing of NAc MSNs (Hakan and Henriksen, 1989;Lee et al, 1999). In the present study, we find that chronic morphine administration, or its resulting suppression of BDNF-TrkB signaling in D1-type MSNs, decreases expression of several GABA A R subunits in this neuronal cell type of the NAc and that the concomitant reduction of inhibitory GABAergic tone in NAc D1-type MSNs promotes morphine reward.…”

Mu-opioid Self-Administration vs Passive Administration in Heroin Abusers Produces Differential EEG Activation

“…EEG activity in animals is greater preceding morphine SA than PA (Grasing and Szeto, 1993). Animals that self-administer vs receive opioids passively show differential electrophysiological activity of cells in the ventral tegmental area (Kiyatkin and Rebec, 2001) and prefrontal cortex (Lee et al, 1999), as well as differences in nucleus accumbens dopamine release (Hemby et al, 1995) and neurotransmitter turnover rates (Smith et al, 1980(Smith et al, , 1982(Smith et al, , 1984a. Chronic morphine SA relative to PA alters acetylcholine and benzodiazepine receptor density (Smith et al, 1984b), and the expression of various proteins (Self et al, 1995) and gene transcripts in the nucleus accumbens shell (Jacobs et al, 2002) but not nucleus accumbens core (Jacobs et al, 2004) relative to chronic PA.…”

“…These initial findings are consistent with preclinical data that self-and passively administered opioids produce different patterns of electrophysiological activity (Chang et al, 1997(Chang et al, , 1998Grasing and Szeto, 1993;Kiyatkin and Rebec, 2001;Lee et al, 1999) and various other neurobiological changes (Jacobs et al, 2003). Fentanyl, a highly potent, short-acting, heroin-like drug with abuse potential in humans (Greenwald et al, 1996;Baylon et al, 2000), functioned as a reinforcer (ie it maintained high rates of responding) in these opioiddependent volunteers.…”

Cannabinoid Modulation of Opiate Reinforcement through the Ventral Striatopallidal Pathway

“…The VP has been implicated in mediating the rewarding effects of opiates and psychostimulants (Johnson et al, 1993;Robledo and Koob, 1993;Johnson and Stellar, 1994;Gong et al, 1996;Bardo, 1998;Stein, 2000, 2002). This region receives dense GABAergic innervation from the NAC (Groenewegen and Russchen, 1984;Chang and Kitai, 1985), and both opiate and psychostimulant drugs inhibit the activity of this projection (Hakan and Henriksen, 1989;Bourdelais and Kalivas, 1990;Bardo, 1998;Lee et al, 1999;Stein, 2000, 2002;Caillé and Parsons, 2004). Consistently, both morphine and cocaine were found to significantly decrease VP GABA efflux in the present study.…”

“…The VP receives a dense GABAergic input from the NAC (Groenewegen and Russchen, 1984;Chang and Kitai, 1985); while the NAC shell projects to the ventromedial part of the VP, the NAC core projects mainly to the dorsolateral part of the VP. Opiates strongly inhibit the spontaneous activity of the NAC GABAergic neurons (Hakan and Henriksen, 1989;Bardo, 1998;Lee et al, 1999;Stein, 2000, 2002) thereby reducing VP GABA efflux (Caillé and Parsons, 2004). The resultant disinhibition of the VP is thought to contribute to the positive reinforcing effects of opiates.…”