‘Hot’ vs. ‘cold’ behavioural‐cognitive styles: motivational‐dopaminergic vs. cognitive‐cholinergic processing of a Pavlovian cocaine cue in sign‐ and goal‐tracking rats

Discrete Pavlovian reward cues acquire more potent incentive motivational properties (incentive salience) in some animals (sign‐trackers; STs) compared to others (goal‐trackers; GTs). Conversely, GTs appear to be better than STs in processing more complex contextual cues, perhaps reflecting their relatively greater bias for goal‐directed cue processing. Here, we investigated the activity of two major prefrontal neuromodulatory input systems, dopamine (DA) and acetylcholine (ACh), in response to a discrete Pavlovian cue that was previously paired with cocaine administration in STs and GTs. Rats underwent Pavlovian training in which light cue presentations were either paired or unpaired with an intravenous cocaine infusion. Following a 10‐day abstinence period, prefrontal dialysates were collected in STs and GTs during cue presentations in the absence of cocaine. In STs, the cue previously paired with cocaine significantly increased prefrontal DA levels. DA levels remained elevated over baseline across multiple cue presentation blocks, and DA levels and approaches to the cue were significantly correlated. In STs, ACh levels were unaffected by cue presentations. In contrast, in GTs, presentations of the cocaine cue increased prefrontal ACh, but not DA, levels. GTs oriented towards the cue at rates similar to STs, but they did not approach it and elevated ACh levels did not correlate with conditioned orientation. The results indicate a double dissociation between the role of prefrontal DA and ACh in STs and GTs, and suggest that these phenotypes will be useful for studying the role of neuromodulator systems in mediating opponent behavioural‐cognitive styles.We investigated the activity of two major prefrontal neuromodulatory input systems, dopamine (DA) and acetylcholine (ACh), in response to a Pavlovian cue that was previously paired with cocaine administration in STs and GTs. Following an abstinence period and in the absence of cocaine, cue presentations (C1–C4) in STs resulted in increases in extracellular DA, but not ACh, levels (left). In contrast, cue presentations in GTs increased ACh, but not DA, levels (NC, no‐cue).Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/1/ejn13741_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/2/ejn13741-sup-0001-reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141035/3/ejn13741.pd

Natural Reward Experience Alters AMPA and NMDA Receptor Distribution and Function in the Nucleus Accumbens

Natural reward and drugs of abuse converge upon the mesolimbic system which mediates motivation and reward behaviors. Drugs induce neural adaptations in this system, including transcriptional, morphological, and synaptic changes, which contribute to the development and expression of drug-related memories and addiction. Previously, it has been reported that sexual experience in male rats, a natural reward behavior, induces similar neuroplasticity in the mesolimbic system and affects natural reward and drug-related behavior. The current study determined whether sexual experience causes long-lasting changes in mating, or ionotropic glutamate receptor trafficking or function in the nucleus accumbens (NAc), following 3 different reward abstinence periods: 1 day, 1 week, or 1 month after final mating session. Male Sprague Dawley rats mated during 5 consecutive days (sexual experience) or remained sexually naïve to serve as controls. Sexually experienced males displayed facilitation of initiation and performance of mating at each time point. Next, intracellular and membrane surface expression of N-methyl-D-aspartate (NMDA: NR1 subunit) and α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA: GluA1, GluA2 subunits) receptors in the NAc was determined using a bis(sulfosuccinimidyl)suberate (BS3) protein cross-linking assay followed by Western Blot analysis. NR1 expression was increased at 1 day abstinence both at surface and intracellular, but decreased at surface at 1 week of abstinence. GluA2 was increased intracellularly at 1 week and increased at the surface after 1 month of abstinence. Finally, whole-cell patch clamp electrophysiological recordings determined reduced AMPA/NMDA ratio of synaptic currents in NAc shell neurons following stimulation of cortical afferents in sexually experienced males after all reward abstinence periods. Together, these data show that sexual experience causes long-term alterations in glutamate receptor expression and function in the NAc. Although not identical, this sex experience-induced neuroplasticity has similarities to that caused by psychostimulants, suggesting common mechanisms for reinforcement of natural and drug reward

Endogenous Opioid-Induced Neuroplasticity of Dopaminergic Neurons in the Ventral Tegmental Area Influences Natural and Opiate Reward

Natural reward and drugs of abuse converge on the mesolimbic pathway and activate common mechanism of neural plasticity in the nucleus accumbens. Chronic exposure to opiates induces plasticity in dopaminergic neurons of the ventral tegmental area (VTA), which regulates morphine reward tolerance. Here, we test the hypotheses that mating-induced release of endogenous opioids in the VTA causes morphological changes of VTA dopamine cells in male rats, which in-turn regulate the long-term expression of experience-induced reinforcement of sexual behavior. First, sexual experience decreased VTA dopamine soma size 1 and 7 days, but not 30 days after the last mating session. This effect was blocked with naloxone before each mating session; thus, VTA dopamine cell plasticity was dependent on action of endogenous opioids. In turn, VTA plasticity was associated with altered opiate reward, as sexually experienced males did not form conditioned place preference for 0.5 mg/kg morphine. Next, it was determined whether endogenous opioid action mediates sexual reward and memory in male rats treated with naloxone during mating experience, either systemically or intra-VTA. Naloxone did not prevent the initial experience-induced facilitation of sexual behavior over repeated mating sessions, or conditioned place preference for mating. However, naloxone treatment attenuated the longer-term expression of experience-induced facilitation of sexual behavior and neural activation in mesolimbic areas induced by mating-associated conditioned cues. Together, these data demonstrate that endogenous opioids during mating induce neural plasticity in VTA dopamine neurons that appear critical for morphine reward and long-term memory for natural reward behavior

Long-term maintenance of facilitated sexual behavior.

<p>Latencies to mount (A), intromission (B), and ejaculation (C) for two experimental groups during 5 daily mating sessions and a final Test either 1 week (white, dashed) or 1 month (black, continuous) following last mating session. Data are expressed as group means (± SEM). * indicates significant difference from Day 1; # indicates significant difference from Day 5.</p

Glutamate receptor subunit expression and distribution in the NAc.

<p>Quantitative analysis of expression for NR1 (A, D, G, J), GluA2 (B, E, H, K) and GluA1 (C, F, J, L) for surface (A, B, C), intracellular (D, E, F), surface to intracellular ratios (G, H, I) and total protein levels (J, K, L) in sexually experienced and naïve males at 1 day, 1 week and 1 month following last mating or handling session. Data are expressed as group means (± SEM). * indicates significant difference from sexually naïve males at same time point. Statistical trends are indicated by p-values. Images of representative blots demonstrating surface (>250 kDa) and intracellular bands for NR1 (∼130 kDa), GluA2 (∼100 kDa) and GluA1 (∼106 kDa) (M). Representative images demonstrating increased surface expression of NR1 (N) and intracellular expression of GluA2 (O) at 1D and 1W respectively.</p