Rats were pretreated with daily cocaine or saline injections for 1 week. The rats treated with daily cocaine were separated into two groups: a sensitized group of animals demonstrating > 20% increase in motor activity on the last injection compared with the first injection of daily cocaine, and a nonsensitized group showing < 20% elevation. At 2-3 weeks after the last daily injection, four experiments were performed to assess changes in excitatory amino acid (EAA) transmission in the nucleus accumbens produced by repeated cocaine administration. (1) Rats were challenged with a microinjection of AMPA into the shell or core of the nucleus accumbens. The sensitized rats demonstrated greater motor activity than did the saline-pretreated or nonsensitized animals after AMPA injection into either subnucleus. (2) It was shown that the behavioral distinction between sensitized, nonsensitized, and control rats in behavioral responsiveness to AMPA was not mediated by differences in AMPA-induced dopamine release. (3) The extracellular content of glutamate was measured after a cocaine challenge given at 21 d of withdrawal. Cocaine elevated the levels of glutamate in the core of sensitized rats, but not of nonsensitized or control rats. (4) Microinjection of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione into the core abolished the augmented motor response to a cocaine challenge in sensitized rats, but was without effect on cocaine-induced motor activity in nonsensitized animals. These results indicate that repeated cocaine administration increases EAA transmission in the nucleus accumbens only in rats that develop behavioral sensitization to cocaine.

Reduced N-methyl-D-aspartate-receptor (NMDAR) signaling has been associated with schizophrenia, autism and intellectual disability. NMDAR-hypofunction is thought to contribute to social, cognitive and gamma (30–80 Hz) oscillatory abnormalities, phenotypes common to these disorders. However, circuit-level mechanisms underlying such deficits remain unclear. This study investigated the relationship between gamma synchrony, excitatory–inhibitory (E/I) signaling, and behavioral phenotypes in NMDA-NR1neo−/− mice, which have constitutively reduced expression of the obligate NR1 subunit to model disrupted developmental NMDAR function. Constitutive NMDAR-hypofunction caused a loss of E/I balance, with an increase in intrinsic pyramidal cell excitability and a selective disruption of parvalbumin-expressing interneurons. Disrupted E/I coupling was associated with deficits in auditory-evoked gamma signal-to-noise ratio (SNR). Gamma-band abnormalities predicted deficits in spatial working memory and social preference, linking cellular changes in E/I signaling to target behaviors. The GABAB-receptor agonist baclofen improved E/I balance, gamma-SNR and broadly reversed behavioral deficits. These data demonstrate a clinically relevant, highly translatable neural-activity-based biomarker for preclinical screening and therapeutic development across a broad range of disorders that share common endophenotypes and disrupted NMDA-receptor signaling.

Increasing evidence suggests that deep brain stimulation (DBS), which is currently being used as a therapy for neurological diseases, may be effective in the treatment of psychiatric disorders as well. Here, we examined the influence of DBS of the nucleus accumbens shell on cocaine priming-induced reinstatement of drug seeking, an animal model of relapse. Rats were allowed to self-administer cocaine (0.25 mg, i.v.) 2 h daily for 21 d and then cocaine-seeking behavior was extinguished by replacing cocaine with saline. During the reinstatement phase, DBS was administered bilaterally to the nucleus accumbens shell through bipolar stainless steel electrodes. Biphasic symmetrical pulses were delivered at a frequency of 160 Hz and a current intensity of 150 A. DBS began immediately after a priming injection of cocaine (0, 5, 10, or 20 mg/kg, i.p.) and continued throughout each 2 h reinstatement session. Results indicated that only the higher doses of cocaine (10 and 20 mg/kg) produced robust and reliable reinstatement of cocaine seeking. DBS of the nucleus accumbens shell significantly attenuated the reinstatement of drug seeking precipitated by these higher cocaine doses. Additional experiments indicated that this DBS effect was both anatomically and reinforcer specific. Thus, DBS of the dorsal striatum had no influence on cocaine reinstatement and DBS of the accumbens shell did not affect the reinstatement of food seeking. Together, these results suggest that DBS of the nucleus accumbens shell may be a potential therapeutic option in the treatment of severe cocaine addiction.

No abstract

Sensitization to cocaine refers to the behavioral model of cocaine addiction where the motor stimulant effect of cocaine is augmented for months after discontinuing a regimen of repeated cocaine injections. There has been speculation that the neuroadaptations mediating this sensitization phenomenon may, in part, underlie the behavioral changes produced by chronic cocaine abuse, including paranoia, craving and relapse. Criteria are proposed that may assist in determining which neuroadaptations are most relevant in this regard. Using these criteria, a model is presented that endeavors to incorporate neuroadaptations issuing directly from the pharmacological effects of cocaine and those arising from learned associations the organism makes with the cocaine injection procedure and pharmacological actions. It is proposed that the pharmacological neuroadaptations predominate in the manifestation of cocaine-induced paranoia, while the changes derived from learning may provide more critical underpinnings for cocaine craving and relapse.

The ability of amylin, a pancreatic b-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose selfadministration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.

No abstract

Enhanced dopamine transmission in the nucleus accumbens plays an important role in cocaine priming-induced reinstatement of drugseeking behavior. However, the contribution of each dopamine receptor subtype to this behavior remains unclear. The present experiments were designed to assess the role of D2-like dopamine receptors in the nucleus accumbens core and shell subregions in cocaine priming-induced reinstatement of drug seeking. Rats were trained to lever press for cocaine using a fixed ratio (FR) 5 schedule of reinforcement. After approximately 18 days of cocaine self-administration, the animals underwent an extinction phase during which cocaine was replaced with saline. Daily extinction sessions were conducted until responding was less than 10% of the response rate maintained by cocaine self-administration. Following the extinction phase, priming-induced reinstatement of cocaine-seeking behavior was assessed. A range of doses of antagonists selective for D2-(sulpiride, 0.2 or 2.0 mg), D3-(U99194A, 3.9 or 7.8 mg), or D4-(L-750,667, 5.5 or 11 mg) dopamine receptors were microinjected into either the nucleus accumbens core, shell or lateral septum prior to a priming injection of cocaine (10 mg/kg, i.p.). Following administration into the shell, but not core or lateral septum, sulpiride dose-dependently attenuated reinstatement induced by a cocaine priming injection. In contrast, U99194A and L-750,667 failed to influence cocaine seeking at any of the doses tested in either accumbal subregion. Collectively, these findings indicate that activation of D2 dopamine receptors mediates cocaine priming-induced reinstatement of cocaine seeking in a region-specific manner within the nucleus accumbens.